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Ruysseveldt E, Steelant B, Wils T, Cremer J, Bullens DMA, Hellings PW, Martens K. The nasal basal cell population shifts toward a diseased phenotype with impaired barrier formation capacity in allergic rhinitis. J Allergy Clin Immunol 2024; 154:631-643. [PMID: 38705259 DOI: 10.1016/j.jaci.2024.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/27/2024] [Accepted: 04/10/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND The integrity of the airway epithelium is guarded by the airway basal cells that serve as progenitor cells and restore wounds in case of injury. Basal cells are a heterogenous population, and specific changes in their behavior are associated with chronic barrier disruption-mechanisms that have not been studied in detail in allergic rhinitis (AR). OBJECTIVE We aimed to study basal cell subtypes in AR and healthy controls. METHODS Single-cell RNA sequencing (scRNA-Seq) of the nasal epithelium was performed on nonallergic and house dust mite-allergic AR patients to reveal basal cell diversity and to identify allergy-related alterations. Flow cytometry, immunofluorescence staining, and in vitro experiments using primary basal cells were performed to confirm phenotypic findings at the protein level and functionally. RESULTS The scRNA-Seq, flow cytometry, and immunofluorescence staining revealed that basal cells are abundantly and heterogeneously present in the nasal epithelium, suggesting specialized subtypes. The total basal cell fraction within the epithelium in AR is increased compared to controls. scRNA-Seq demonstrated that potentially beneficial basal cells are missing in AR epithelium, while an activated population of allergy-associated basal cells is more dominantly present. Furthermore, our in vitro proliferation, wound healing assay and air-liquid interface cultures show that AR-associated basal cells have altered progenitor capacity compared to nonallergic basal cells. CONCLUSIONS The nasal basal cell population is abundant and diverse, and it shifts toward a diseased state in AR. The absence of potentially protective subtypes and the rise of a proinflammatory population suggest that basal cells are important players in maintaining epithelial barrier defects in AR.
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Affiliation(s)
- Emma Ruysseveldt
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.
| | - Brecht Steelant
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | - Tine Wils
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | - Jonathan Cremer
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | - Dominique M A Bullens
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Clinical Department of Paediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Peter W Hellings
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Clinical Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Upper Airways Research Laboratory, University of Ghent, Ghent, Belgium
| | - Katleen Martens
- Department of Microbiology, Immunology, and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Department of Bioscience Engineering, Research Group Environmental Ecology and Applied Microbiology, University of Antwerp, Antwerp, Belgium
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Tian E, Syed ZA, Edin ML, Zeldin DC, Ten Hagen KG. Dynamic expression of mucins and the genes controlling mucin-type O-glycosylation within the mouse respiratory system. Glycobiology 2023; 33:476-489. [PMID: 37115803 PMCID: PMC10284109 DOI: 10.1093/glycob/cwad031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/22/2023] [Indexed: 04/29/2023] Open
Abstract
The COVID-19 global pandemic has underscored the need to understand how viruses and other pathogens are able to infect and replicate within the respiratory system. Recent studies have highlighted the role of highly O-glycosylated mucins in the protection of the respiratory system as well as how mucin-type O-glycosylation may be able to modify viral infectivity. Therefore, we set out to identify the specific genes controlling mucin-type O-glycosylation throughout the mouse respiratory system as well as determine how their expression and the expression of respiratory mucins is influenced by infection or injury. Here, we show that certain mucins and members of the Galnt family are abundantly expressed in specific respiratory tissues/cells and demonstrate unique patterns of O-glycosylation across diverse respiratory tissues. Moreover, we find that the expression of certain Galnts and mucins is altered during lung infection and injury in experimental mice challenged with infectious agents, toxins, and allergens. Finally, we examine gene expression changes of Galnts and mucins in a mouse model of SARS-CoV-2 infection. Our work provides foundational knowledge regarding the specific expression of Galnt enzyme family members and mucins throughout the respiratory system, and how their expression is altered upon lung infection and injury.
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Affiliation(s)
- E Tian
- Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370, USA
| | - Zulfeqhar A Syed
- Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370, USA
| | - Matthew L Edin
- Division of Intramural Research, NIEHS, National Institutes of Health, Research Triangle Park, Durham, NC 27514, USA
| | - Darryl C Zeldin
- Division of Intramural Research, NIEHS, National Institutes of Health, Research Triangle Park, Durham, NC 27514, USA
| | - Kelly G Ten Hagen
- Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370, USA
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3
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Robb CT, Zhou Y, Felton JM, Zhang B, Goepp M, Jheeta P, Smyth DJ, Duffin R, Vermeren S, Breyer R, Narumiya S, McSorley HJ, Maizels RM, Schwarze JKJ, Rossi AG, Yao C. Metabolic regulation by prostaglandin E 2 impairs lung group 2 innate lymphoid cell responses. Allergy 2023; 78:714-730. [PMID: 36181709 PMCID: PMC10952163 DOI: 10.1111/all.15541] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 09/15/2022] [Accepted: 09/18/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2 ). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. METHODS The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures. RESULTS Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2 -EP2 signaling. CONCLUSION We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.
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Affiliation(s)
- Calum T. Robb
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - You Zhou
- Systems Immunity University Research Institute and Division of Infection and ImmunityCardiff UniversityCardiffUK
| | - Jennifer M. Felton
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Birong Zhang
- Systems Immunity University Research Institute and Division of Infection and ImmunityCardiff UniversityCardiffUK
| | - Marie Goepp
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Privjyot Jheeta
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Danielle J. Smyth
- Division of Cell Signaling and Immunology, School of Life SciencesWellcome Trust Building, University of DundeeDundeeUK
| | - Rodger Duffin
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Sonja Vermeren
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Richard M. Breyer
- Department of Veterans AffairsTennessee Valley Health AuthorityNashvilleTennesseeUSA
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Shuh Narumiya
- Alliance Laboratory for Advanced Medical Research and Department of Drug Discovery Medicine, Medical Innovation CenterKyoto University Graduate School of MedicineKyotoJapan
| | - Henry J. McSorley
- Division of Cell Signaling and Immunology, School of Life SciencesWellcome Trust Building, University of DundeeDundeeUK
| | - Rick M. Maizels
- Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and InflammationUniversity of GlasgowGlasgowUK
| | - Jürgen K. J. Schwarze
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Adriano G. Rossi
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Chengcan Yao
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
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Yadav SK, Sharma P, Shah SD, Panettieri RA, Kambayashi T, Penn RB, Deshpande DA. Autocrine regulation of airway smooth muscle contraction by diacylglycerol kinase. J Cell Physiol 2022; 237:603-616. [PMID: 34278583 PMCID: PMC8763953 DOI: 10.1002/jcp.30528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/01/2021] [Accepted: 07/06/2021] [Indexed: 01/03/2023]
Abstract
Diacylglycerol kinase (DGK), a lipid kinase, catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid, thereby terminating DAG-mediated signaling by Gq-coupled receptors that regulate contraction of airway smooth muscle (ASM). A previous study from our laboratory demonstrated that DGK inhibition or genetic ablation leads to reduced ASM contraction and provides protection for allergen-induced airway hyperresponsiveness. However, the mechanism by which DGK regulates contractile signaling in ASM is not well established. Herein, we investigated the role of prorelaxant cAMP-protein kinase A (PKA) signaling in DGK-mediated regulation of ASM contraction. Pretreatment of human ASM cells with DGK inhibitor I activated PKA as demonstrated by the phosphorylation of PKA substrates, VASP, Hsp20, and CREB, which was abrogated when PKA was inhibited pharmacologically or molecularly using overexpression of the PKA inhibitor peptide, PKI. Furthermore, inhibition of DGK resulted in induction of cyclooxygenase (COX) and generation of prostaglandin E2 (PGE2 ) with concomitant activation of Gs-cAMP-PKA signaling in ASM cells in an autocrine/paracrine fashion. Inhibition of protein kinase C (PKC) or extracellular-signal-regulated kinase (ERK) attenuated DGK-mediated production of PGE2 and activation of cAMP-PKA signaling in human ASM cells, suggesting that inhibition of DGK activates the COX-PGE2 pathway in a PKC-ERK-dependent manner. Finally, DGK inhibition-mediated attenuation of contractile agonist-induced phosphorylation of myosin light chain 20 (MLC-20), a marker of ASM contraction, involves COX-mediated cAMP production and PKA activation in ASM cells. Collectively these findings establish a novel mechanism by which DGK regulates ASM contraction and further advances DGK as a potential therapeutic target to provide effective bronchoprotection in asthma.
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Affiliation(s)
- Santosh K. Yadav
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA 19107
| | - Pawan Sharma
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA 19107
| | - Sushrut D. Shah
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA 19107
| | - Reynold A. Panettieri
- Rutgers Institute for Translational Medicine & Science, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901
| | - Taku Kambayashi
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Raymond B. Penn
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA 19107
| | - Deepak A. Deshpande
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA 19107
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Eicosanoid receptors as therapeutic targets for asthma. Clin Sci (Lond) 2021; 135:1945-1980. [PMID: 34401905 DOI: 10.1042/cs20190657] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022]
Abstract
Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.
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6
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PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness. J Allergy Clin Immunol 2020; 146:1387-1396.e13. [DOI: 10.1016/j.jaci.2020.03.046] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 03/22/2020] [Accepted: 03/31/2020] [Indexed: 12/12/2022]
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Wu J, Wang Y, Zhou Y, Wang Y, Sun X, Zhao Y, Guan Y, Zhang Y, Wang W. PPARγ as an E3 Ubiquitin-Ligase Impedes Phosphate-Stat6 Stability and Promotes Prostaglandins E 2-Mediated Inhibition of IgE Production in Asthma. Front Immunol 2020; 11:1224. [PMID: 32636842 PMCID: PMC7317005 DOI: 10.3389/fimmu.2020.01224] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/15/2020] [Indexed: 12/18/2022] Open
Abstract
Increased serum IgE level is one of the features of allergic asthma. It is reported that IgE production can be enhanced by E-prostanoid 2 (EP2) receptor of prostaglandin E2 (PGE2); however, whether E-prostanoid 4 (EP4) receptor (encoded by Ptger4) has a unique or redundant role is still unclear. Here, we demonstrated the mice with B cell-specific deletion of the EP4 receptor (Ptger4fl/flMb1cre+/−) showed their serum levels of IgE were markedly increased. A much more severe airway allergic inflammation was observed in the absence of EP4 signal using the OVA-induced asthma model. Mechanistic studies demonstrated that the transcription levels of AID, GLTε, and PSTε in EP4-deficient B cells were found to be significantly increased, implying an enhanced IgE class switch. In addition, we saw higher levels of phosphorylated STAT6, a vital factor for IgE class switch. Biochemical analyses indicated that inhibitory effect of EP4 signal on IgE depended on the activation of the PI3K-AKT pathway. Further downstream, PPARγ expression was up-regulated. Independent of its activity as a transcription factor, PPARγ here primarily functioned as an E3 ubiquitin-ligase, which bound the phosphorylated STAT6 to initiate its degradation. In support of PPARγ as a key mediator downstream of the EP4 signal, PPARγ agonist induced the down-regulation of phospho-STAT6, whereas its antagonist was able to rescue the EP4-mediated inhibition of STAT6 activation and IgE production. Thus, our findings highlight a role for the PGE2-EP4-AKT-PPARγ-STAT6 signaling in IgE response, highlighting the therapeutic potential of combined application of EP4 and PPARγ agonists in asthma.
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Affiliation(s)
- Jia Wu
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yu Zhou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuqing Wang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Xiaowan Sun
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Ye Zhao
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Yu Zhang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China.,Institute of Biological Sciences, Jinzhou Medical University, Jinzhou, China
| | - Wei Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
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8
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Caspase-11 promotes allergic airway inflammation. Nat Commun 2020; 11:1055. [PMID: 32103022 PMCID: PMC7044193 DOI: 10.1038/s41467-020-14945-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 02/12/2020] [Indexed: 11/29/2022] Open
Abstract
Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma. Caspase 11 activation involves transcriptional upregulation and proteolytic cleavage. Here the authors show that prostaglandin E2 prevents caspase-11-mediated pyroptosis, blocking caspase-11 mRNA and protein upregulation in macrophages and in vivo, and that mice lacking caspase-11 are strongly protected from allergic airway inflammation.
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9
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Plaza J, Torres R, Urbano A, Picado C, de Mora F. In Vitro and In Vivo Validation of EP2-Receptor Agonism to Selectively Achieve Inhibition of Mast Cell Activity. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:712-728. [PMID: 32400135 PMCID: PMC7225001 DOI: 10.4168/aair.2020.12.4.712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/27/2020] [Accepted: 03/01/2020] [Indexed: 02/01/2023]
Abstract
Purpose Agonism of the prostaglandin E2 receptor, E-prostanoid receptor 2 (EP2), may represent an alternative protective mechanism in mast cell (MC)-mediated diseases. Previous studies have suggested that activation of the MC EP2 receptor prevents pathological changes in the murine models of allergic asthma. This work aimed to analytically validate the EP2 receptor on MCs as a therapeutic target. Methods Murine MC lines and primary cultures, and MCs bearing the human immunoglobulin E (IgE) receptor were subjected to IgE-mediated activation subsequent to incubation with selective EP2 agonists. Two molecularly unrelated agonists, butaprost and CP-533536, were tested either in vitro or in 2 in vivo models of allergy. Results The diverse range of MC populations was consistently inhibited through selective EP2 agonism in spite of exhibiting a heterogeneous phenotype. Such inhibition occurred in both mouse and human IgE (hIgE)-mediated activation. The use of molecularly unrelated selective EP2 agonists allowed for the confirmation of the specificity of this protective mechanism. This effect was further demonstrated in 2 in vivo murine models of allergy where MCs are a key to pathological changes: cutaneous anaphylaxis in a transgenic mouse model expressing the hIgE receptor and aeroallergen-induced murine model of asthma. Conclusions Selective EP2 agonism is a powerful pharmacological strategy to prevent MCs from being activated through IgE-mediated mechanisms and from causing deleterious effects. The MC EP2 receptor may be an effective pharmacological target in allergic and other MC-mediated conditions.
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Affiliation(s)
- Judith Plaza
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rosa Torres
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Adrián Urbano
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - César Picado
- Department of Pneumology and Respiratory Allergy, Hospital Clínic i Universitari de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
| | - Fernando de Mora
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.
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10
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Qian F, Misra S, Prabhu KS. Selenium and selenoproteins in prostanoid metabolism and immunity. Crit Rev Biochem Mol Biol 2019; 54:484-516. [PMID: 31996052 PMCID: PMC7122104 DOI: 10.1080/10409238.2020.1717430] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 02/06/2023]
Abstract
Selenium (Se) is an essential trace element that functions in the form of the 21st amino acid, selenocysteine (Sec) in a defined set of proteins. Se deficiency is associated with pathological conditions in humans and animals, where incorporation of Sec into selenoproteins is reduced along with their expression and catalytic activity. Supplementation of Se-deficient population with Se has shown health benefits suggesting the importance of Se in physiology. An interesting paradigm to explain, in part, the health benefits of Se stems from the observations that selenoprotein-dependent modulation of inflammation and efficient resolution of inflammation relies on mechanisms involving a group of bioactive lipid mediators, prostanoids, which orchestrate a concerted action toward maintenance and restoration of homeostatic immune responses. Such an effect involves the interaction of various immune cells with these lipid mediators where cellular redox gatekeeper functions of selenoproteins further aid in not only dampening inflammation, but also initiating an effective and active resolution process. Here we have summarized the current literature on the multifaceted roles of Se/selenoproteins in the regulation of these bioactive lipid mediators and their immunomodulatory effects.
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Affiliation(s)
- Fenghua Qian
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences and The Penn State Cancer Institute, The Pennsylvania State University, University Park, PA. 16802, USA
| | - Sougat Misra
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences and The Penn State Cancer Institute, The Pennsylvania State University, University Park, PA. 16802, USA
| | - K. Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences and The Penn State Cancer Institute, The Pennsylvania State University, University Park, PA. 16802, USA
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11
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Maruyama N, Takai T, Kamijo S, Suchiva P, Ohba M, Takeshige T, Suzuki M, Hara M, Matsuno K, Harada S, Harada N, Nakae S, Sudo K, Okuno T, Yokomizo T, Ogawa H, Okumura K, Ikeda S. Cyclooxygenase inhibition in mice heightens adaptive- and innate-type responses against inhaled protease allergen and IL-33. Allergy 2019; 74:2237-2240. [PMID: 31006115 DOI: 10.1111/all.13831] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Natsuko Maruyama
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
- Department of Dermatology and Allergology Juntendo University Graduate School of Medicine Tokyo Japan
| | - Toshiro Takai
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Seiji Kamijo
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Punyada Suchiva
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
- Department of Dermatology and Allergology Juntendo University Graduate School of Medicine Tokyo Japan
| | - Mai Ohba
- Department of Biochemistry Juntendo University Graduate School of Medicine Tokyo Japan
| | - Tomohito Takeshige
- Department of Respiratory Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Mayu Suzuki
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Mutsuko Hara
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Kei Matsuno
- Department of Respiratory Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Sonoko Harada
- Department of Respiratory Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Norihiro Harada
- Department of Respiratory Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Susumu Nakae
- Laboratory of Systems Biology Center for Experimental Medicine and Systems Biology The Institute of Medical Science The University of Tokyo Tokyo Japan
| | - Katsuko Sudo
- Pre‐clinical Research Center Tokyo Medical University Tokyo Japan
| | - Toshiaki Okuno
- Department of Biochemistry Juntendo University Graduate School of Medicine Tokyo Japan
| | - Takehiko Yokomizo
- Department of Biochemistry Juntendo University Graduate School of Medicine Tokyo Japan
| | - Hideoki Ogawa
- Department of Dermatology and Allergology Juntendo University Graduate School of Medicine Tokyo Japan
| | - Ko Okumura
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Shigaku Ikeda
- Atopy (Allergy) Research Center Juntendo University Graduate School of Medicine Tokyo Japan
- Department of Dermatology and Allergology Juntendo University Graduate School of Medicine Tokyo Japan
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12
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Miyata J, Fukunaga K, Kawashima Y, Watanabe T, Saitoh A, Hirosaki T, Araki Y, Kikawada T, Betsuyaku T, Ohara O, Arita M. Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis. Allergy 2019; 74:1113-1124. [PMID: 30667533 DOI: 10.1111/all.13726] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/29/2018] [Accepted: 12/17/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Eosinophils are multifunctional granulocytes capable of releasing various cytokines, chemokines, and lipid mediators. We previously reported dysregulated fatty acid metabolism in peripheral blood-derived eosinophils from patients with severe asthma. However, functional characteristics of eosinophils present in allergic inflammatory tissues remain largely uncharacterized. METHODS We established a method for isolating CD69hi CCR3low CXCR4- siglec-8int eosinophils from nasal polyps of patients with eosinophilic rhinosinusitis (NP-EOS). Multi-omics analysis including lipidomics, proteomics, and transcriptomics was performed to analyze NP-EOS as compared to peripheral blood-derived eosinophils from healthy subjects (PB-EOS). RESULTS Lipidomic analysis revealed impaired synthesis of prostaglandins and 15-lipoxygenase (15-LOX)-derived mediators, and selective upregulation of leukotriene D4 production. Furthermore, proteomics and transcriptomics revealed changes in the expression of specific enzymes (GGT5, DPEP2, and 15-LOX) responsible for dysregulated lipid metabolism. Ingenuity pathway analysis indicated the importance of type 2 cytokines and pattern recognition receptor pathways. Stimulation of PB-EOS with eosinophil activators IL-5, GM-CSF, and agonists of TLR2 and NOD2 mimicked the observed changes in lipid metabolism. CONCLUSION Inflammatory tissue-derived eosinophils possess a specific phenotype with dysregulated fatty acid metabolism that may be targeted therapeutically to control eosinophilic inflammatory diseases.
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Affiliation(s)
- Jun Miyata
- Laboratory for Metabolomics RIKEN Center for Integrative Medical Sciences Kanagawa Japan
- Graduate School of Medical Life Science Yokohama City University Kanagawa Japan
- Division of Pulmonary Medicine Department of Medicine Keio University School of Medicine Tokyo Japan
| | - Koichi Fukunaga
- Division of Pulmonary Medicine Department of Medicine Keio University School of Medicine Tokyo Japan
| | - Yusuke Kawashima
- Laboratory for Integrative Genomics RIKEN Center for Integrative Medical Sciences Yokohama Japan
| | - Takashi Watanabe
- Laboratory for Integrative Genomics RIKEN Center for Integrative Medical Sciences Yokohama Japan
| | - Akina Saitoh
- Tsukuba Research Institute Ono Pharmaceutical Co., Ltd. Tsukuba Japan
| | - Tomomi Hirosaki
- Minase Research Institute Ono Pharmaceutical Co., Ltd. Osaka Japan
| | | | | | - Tomoko Betsuyaku
- Division of Pulmonary Medicine Department of Medicine Keio University School of Medicine Tokyo Japan
| | - Osamu Ohara
- Laboratory for Integrative Genomics RIKEN Center for Integrative Medical Sciences Yokohama Japan
| | - Makoto Arita
- Laboratory for Metabolomics RIKEN Center for Integrative Medical Sciences Kanagawa Japan
- Graduate School of Medical Life Science Yokohama City University Kanagawa Japan
- Division of Physiological Chemistry and Metabolism Faculty of Pharmacy Keio University Tokyo Japan
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13
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Xia H, He Q, Wang H, Wang Y, Yang Y, Li Y, Zhang J, Chen Z, Yang J. Treatment with either COX-2 inhibitor or 5-LOX inhibitor causes no compensation between COX-2 pathway and 5-LOX pathway in chronic aluminum overload-induced liver injury in rats. Fundam Clin Pharmacol 2019; 33:535-543. [PMID: 30903708 DOI: 10.1111/fcp.12465] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 03/04/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023]
Abstract
This study was designed to observe the compensation between cyclooxygenase-2 pathway and 5-lipoxygenase pathway in chronic aluminum overload-induced liver injury rats. A rat hepatic injury model of chronic aluminum injury was established by the intragastric administration of aluminum gluconate (Al3 + 200 mg/kg per day, 5 days a week for 20 weeks). The COX-2 inhibitor [meloxicam (1 mg/kg)] and 5-LOX inhibitor [caffeic acid (30 mg/kg)] were intragastrically administered 1 h after aluminum administration. The histopathology was detected by hematoxylin-eosin staining. A series of biochemical indicators were measured with biochemistry assay or ELISAs. The expressions of COX-2 and 5-LOX were measured by immunohistochemistry. Our experimental results showed that aluminum overload caused a significant damage to the liver and also significantly increased the expressions of COX-2, 5-LOX and the levels of inflammation and oxidative stress. The administration of meloxicam and caffeic acid significantly protected livers against histopathological injury, significantly decreased plasma ALT, AST, and ALP levels, significantly decreased TNF-α, IL-6, IL-1β levels, and oxidative stress. However, the administration of caffeic acid did not significantly increase the expression of COX-2 compared with the model group. On the other hand, the administration of meloxicam also did not significantly increase the expression of 5-LOX compared with the model group. Our results indicate that there is no compensation between COX-2 pathway and 5-LOX pathway by inhibiting either COX-2 or 5-LOX in chronic aluminum overload-induced liver injury rat.
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Affiliation(s)
- Hui Xia
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Qin He
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hong Wang
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Yongming Wang
- Department of Neonatalogy, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Yang Yang
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Yuke Li
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Jiahua Zhang
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Zhihao Chen
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Junqing Yang
- Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
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14
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Robichaux WG, Cheng X. Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiol Rev 2018; 98:919-1053. [PMID: 29537337 PMCID: PMC6050347 DOI: 10.1152/physrev.00025.2017] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 09/05/2017] [Accepted: 09/06/2017] [Indexed: 12/13/2022] Open
Abstract
This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.
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Affiliation(s)
- William G Robichaux
- Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center , Houston, Texas
| | - Xiaodong Cheng
- Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center , Houston, Texas
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15
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Zhou Y, Wang W, Zhao C, Wang Y, Wu H, Sun X, Guan Y, Zhang Y. Prostaglandin E 2 Inhibits Group 2 Innate Lymphoid Cell Activation and Allergic Airway Inflammation Through E-Prostanoid 4-Cyclic Adenosine Monophosphate Signaling. Front Immunol 2018; 9:501. [PMID: 29593738 PMCID: PMC5857904 DOI: 10.3389/fimmu.2018.00501] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 02/26/2018] [Indexed: 12/31/2022] Open
Abstract
Evidence is accumulating that group 2 innate lymphoid cells (ILC2) play an important role in allergic airway inflammation by producing a large amount of type 2 cytokines. But it remains poorly understood how its activities are properly controlled in vivo. Here, we demonstrated that prostaglandin E2 (PGE2) had a profound inhibitory effect on IL-33-induced ILC2 expansion and IL-5 and IL-13 production in vitro. This effect was mimicked by PGE1-alcohol but attenuated by ONO-AE3-208, indicating a selective action through the E-prostanoid 4 (EP4) receptor. In the IL-33-induced asthma model, coadministration of PGE2 or PGE1-alcohol resulted in diminished IL-5 and IL-13 production, reduced eosinophilia and alleviated lung pathology. In contrast, EP4-deficient mice displayed an exacerbated inflammatory response in another ILC2-mediated asthma model induced by Alternaria extract. Mechanistic studies demonstrated that the PGE2-mediated inhibition of ILC2 was dependent on cyclic adenosine monophosphate (cAMP) production. Further downstream, PGE2-EP4-cAMP signaling led to suppression of GATA3 and ST2 expression, which is known to be critical for ILC2 activation. These findings reveal a novel function of PGE2 as a negative regulator of ILC2 activation and highlight an endogenous counter-regulatory mechanism for the control of innate allergic inflammatory responses.
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Affiliation(s)
- Yu Zhou
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Beijing, China
| | - Wei Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Beijing, China
| | - Conghui Zhao
- Department of Oral Pathology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Yan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Beijing, China
| | - Haoming Wu
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Beijing, China
| | - Xiuyuan Sun
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Beijing, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Yu Zhang
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology, Ministry of Health (Peking University), Beijing, China.,Institute of Biological Sciences, Jinzhou Medical University, Jinzhou, China
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16
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Antony VB, Redlich CA, Pinkerton KE, Balmes J, Harkema JR. National Institute of Environmental Health Sciences: 50 Years of Advancing Science and Improving Lung Health. Am J Respir Crit Care Med 2017; 194:1190-1195. [PMID: 27668911 DOI: 10.1164/rccm.201608-1645pp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The American Thoracic Society celebrates the 50th anniversary of the National Institute of Environmental Health Sciences (NIEHS). The NIEHS has had enormous impact through its focus on research, training, and translational science on lung health. It has been an advocate for clean air both in the United States and across the world. The cutting-edge science funded by the NIEHS has led to major discoveries that have broadened our understanding of the pathogenesis and treatment for lung disease. Importantly, the NIEHS has developed and fostered mechanisms that require cross-cutting science across the spectrum of areas of inquiry, bringing together environmental and social scientists with clinicians to bring their expertise on specific areas of investigation. The intramural program of the NIEHS nurtures cutting-edge science, and the extramural program encourages investigator-initiated research while at the same time providing broader direction through important initiatives. Under the umbrella of the NIEHS and guided by Dr. Linda Birnbaum, the director of the NIEHS, important collaborative programs, such as the Superfund Program and the National Toxicology Program, work to discover mechanisms to protect from environmental toxins. The American Thoracic Society has overlapping goals with the NIEHS, and the strategic plans of both august bodies converge to synergize on population lung health. These bonds must be tightened and highlighted as we work toward our common goals.
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Affiliation(s)
- Veena B Antony
- 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Carrie A Redlich
- 2 Occupational and Environmental Medicine, Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Kent E Pinkerton
- 3 School of Veterinary Medicine, University of California Davis, Davis, California
| | - John Balmes
- 4 Occupational and Environmental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California; and
| | - Jack R Harkema
- 5 Department of Pathology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
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17
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Peinhaupt M, Sturm EM, Heinemann A. Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets. Front Med (Lausanne) 2017; 4:104. [PMID: 28770200 PMCID: PMC5515835 DOI: 10.3389/fmed.2017.00104] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 06/27/2017] [Indexed: 02/06/2023] Open
Abstract
Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention.
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Affiliation(s)
- Miriam Peinhaupt
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Eva M Sturm
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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18
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Jayaraja S, Dakhama A, Yun B, Ghosh M, Lee H, Redente EF, Uhlson CL, Murphy RC, Leslie CC. Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection. BMC Immunol 2016; 17:27. [PMID: 27501951 PMCID: PMC4977843 DOI: 10.1186/s12865-016-0165-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 07/25/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The lung is exposed to airborne fungal spores, and fungi that colonize the oral cavity such as Candida albicans, but does not develop disease to opportunistic fungal pathogens unless the immune system is compromised. The Group IVA cytosolic phospholipase A2 (cPLA2α) is activated in response to Candida albicans infection resulting in the release of arachidonic acid for eicosanoid production. Although eicosanoids such as prostaglandins and leukotrienes modulate inflammation and immune responses, the role of cPLA2α and eicosanoids in regulating C. albicans lung infection is not understood. METHODS The responses of cPLA2α(+/+) and cPLA2α(-/-) Balb/c mice to intratracheal instillation of C. albicans were compared. After challenge, we evaluated weight loss, organ fungal burden, and the recruitment of cells and the levels of cytokines and eicosanoids in bronchoalveolar lavage fluid. The ability of macrophages and neutrophils from cPLA2α(+/+) and cPLA2α(-/-) mice to recognize and kill C. albicans was also compared. RESULTS After C. albicans instillation, cPLA2α(+/+) mice recovered a modest weight loss by 48 h and completely cleared fungi from the lung by 12 h with no dissemination to the kidneys. In cPLA2α(-/-) mice, weight loss continued for 72 h, C. albicans was not completely cleared from the lung and disseminated to the kidneys. cPLA2α(-/-) mice exhibited greater signs of inflammation including higher neutrophil influx, and elevated levels of albumin and pro-inflammatory cytokines/chemokines (IL1α, IL1β, TNFα, IL6, CSF2, CXCL1, CCL20) in bronchoalveolar lavage fluid. The amounts of cysteinyl leukotrienes, thromboxane B2 and prostaglandin E2 were significantly lower in bronchoalveolar lavage fluid from C. albicans-infected cPLA2α(-/-) mice compared to cPLA2α(+/+) mice. Alveolar macrophages and neutrophils from uninfected cPLA2α(-/-) mice exhibited less killing of C. albicans in vitro than cells from cPLA2α(+/+) mice. In addition alveolar macrophages from cPLA2α(-/-) mice isolated 6 h after instillation of GFP-C. albicans contained fewer internalized fungi than cPLA2α(+/+) macrophages. CONCLUSIONS The results demonstrate that cPLA2α contributes to immune surveillance and host defense in the lung to prevent infection by the commensal fungus C. albicans and to dampen inflammation.
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Affiliation(s)
- Sabarirajan Jayaraja
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA
| | - Azzeddine Dakhama
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA
| | - Bogeon Yun
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA
| | - Moumita Ghosh
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA
| | - HeeJung Lee
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA
| | - Elizabeth F Redente
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA
| | - Charis L Uhlson
- Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA
| | - Robert C Murphy
- Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA
| | - Christina C Leslie
- Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA. .,Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA. .,Department of Pathology, University of Colorado Denver, Aurora, Colorado, USA.
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19
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Zhou W, Zhang J, Goleniewska K, Dulek DE, Toki S, Newcomb DC, Cephus JY, Collins RD, Wu P, Boothby MR, Peebles RS. Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation. THE JOURNAL OF IMMUNOLOGY 2016; 197:1577-86. [PMID: 27456482 DOI: 10.4049/jimmunol.1501063] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 06/20/2016] [Indexed: 12/12/2022]
Abstract
Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration-approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.
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Affiliation(s)
- Weisong Zhou
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Jian Zhang
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Kasia Goleniewska
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Daniel E Dulek
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Shinji Toki
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Dawn C Newcomb
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Jacqueline Y Cephus
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Robert D Collins
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Pingsheng Wu
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
| | - Mark R Boothby
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - R Stokes Peebles
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
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20
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Serra-Pages M, Torres R, Plaza J, Herrerias A, Costa-Farré C, Marco A, Jiménez M, Maurer M, Picado C, de Mora F. Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity. Clin Exp Allergy 2016; 45:1590-600. [PMID: 25823713 DOI: 10.1111/cea.12542] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 03/02/2015] [Accepted: 03/03/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro. OBJECTIVE To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC. METHODS Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC-mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4-dinitrophenol (DNP). RESULTS Selective EP2 agonism attenuated aeroallergen-caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation. CONCLUSIONS & CLINICAL RELEVANCE The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen-sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis.
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Affiliation(s)
- M Serra-Pages
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - R Torres
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Plaza
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain
| | - A Herrerias
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - C Costa-Farré
- Department of Surgery and Animals Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - A Marco
- Department of Surgery and Animals Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Jiménez
- Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Hepáticas y Digestivas
| | - M Maurer
- Department of Dermatology, Charité -Universitätsmedizin Berlin, Berlin, Germany
| | - C Picado
- CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.,Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Universitat de Barcelona, Barcelona, Spain
| | - F de Mora
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
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21
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Zhou W, Toki S, Zhang J, Goleniewksa K, Newcomb DC, Cephus JY, Dulek DE, Bloodworth MH, Stier MT, Polosuhkin V, Gangula RD, Mallal SA, Broide DH, Peebles RS. Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 2016; 193:31-42. [PMID: 26378386 DOI: 10.1164/rccm.201410-1793oc] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
RATIONALE Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines central to the asthma phenotype; however, the effect of prostaglandin (PG) I2 on ILC2 function is unknown. OBJECTIVES To determine the effect of PGI2 on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI2 and the PGI2 analog cicaprost on lung ILC2s in vivo. METHODS Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI2 receptor-deficient (IP(-/-)) mice were cultured with IL-33 and treated with the PGI2 analog cicaprost. WT and IP(-/-) mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI2 analog cicaprost. MEASUREMENT AND MAIN RESULTS We demonstrate that PGI2 inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI2 receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI2 signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI2 analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI2 analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33. CONCLUSIONS These results suggest that PGI2 may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.
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Affiliation(s)
- Weisong Zhou
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Shinji Toki
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Jian Zhang
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Kasia Goleniewksa
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Dawn C Newcomb
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Jacqueline Y Cephus
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Daniel E Dulek
- 2 Division of Infectious Diseases, Department of Pediatrics, and
| | - Melissa H Bloodworth
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Matthew T Stier
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Vasiliy Polosuhkin
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
| | - Rama D Gangula
- 3 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and
| | - Simon A Mallal
- 3 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and
| | - David H Broide
- 4 Department of Medicine, University of California San Diego, La Jolla, California
| | - R Stokes Peebles
- 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine
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22
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Gao Y, Zhao C, Wang W, Jin R, Li Q, Ge Q, Guan Y, Zhang Y. Prostaglandins E2 signal mediated by receptor subtype EP2 promotes IgE production in vivo and contributes to asthma development. Sci Rep 2016; 6:20505. [PMID: 26852804 PMCID: PMC4744937 DOI: 10.1038/srep20505] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 01/05/2016] [Indexed: 01/06/2023] Open
Abstract
Prostaglandins E2 (PGE2) has been shown to enhance IgE production by B cells in vitro. The physiological and pathological relevance of this phenomenon and the underlying molecular mechanism, however, remain to be elucidated. B cells from wild type and EP2-deficient mice were compared in culture for their responses to PGE2 in terms of IgE class switching and production. Ovalbumin (OVA)-induced asthma models were used to evaluate the impact of EP2-deficiency on IgE responses and the development of asthma. PGE2 promoted IgE class switching, generation of IgE+ cells and secretion of IgE by B cells stimulated with LPS+IL4. These effects were much attenuated as a consequence of EP2 deficiency. Consistent with the in vitro data, EP2-deficient mice showed a markedly suppressed IgE antibody response and developed less pronounced airway inflammation in the OVA-induced asthma model. Mechanistic studies demonstrated that PGE2, in an EP2-depedent manner, enhanced STAT6 activation induced by IL-4, thereby promoting the expression of IgE germline and post switch transcripts and the transcription of activation-induced cytidine deaminase (AID). Collectively, these data support an important regulatory role of the PGE2-EP2-STAT6 signaling pathway in IgE response and allergic diseases.
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Affiliation(s)
- Yuhan Gao
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China
| | - Chunyan Zhao
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China
| | - Wei Wang
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China
| | - Rong Jin
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China
| | - Qian Li
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China
| | - Qing Ge
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Yu Zhang
- Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Public Health, Peking University Health Science Center, Beijing, China.,State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
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23
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Chen M, Hegde A, Choi YH, Theriot BS, Premont RT, Chen W, Walker JKL. Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model. Am J Respir Cell Mol Biol 2015; 53:346-54. [PMID: 25569510 DOI: 10.1165/rcmb.2014-0231oc] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
β-Arrestin-2 (βarr2) is a ubiquitously expressed cytosolic protein that terminates G protein-coupled receptor signaling and transduces G protein-independent signaling. We previously showed that mice lacking βarr2 do not develop an asthma phenotype when sensitized to, and challenged with, allergens. The current study evaluates if an established asthma phenotype can be mitigated by deletion of βarr2 using an inducible Cre recombinase. We sensitized and challenged mice to ovalbumin (OVA) and demonstrated that on Day (d) 24 the allergic asthma phenotype was apparent in uninduced βarr2 and wild-type (WT) mice. In a second group of OVA-treated mice, tamoxifen was injected on d24 to d28 to activate Cre recombinase, and OVA aerosol challenge was continued through d44. The asthma phenotype was assessed using lung mechanics measurements, bronchoalveolar lavage cell analysis, and histological assessment of mucin and airway inflammation. Compared with their respective saline-treated controls, OVA-treated WT mice and mice expressing the inducible Cre recombinase displayed a significant asthma phenotype at d45. Whereas tamoxifen treatment had no significant effect on the asthma phenotype in WT mice, it inhibited βarr2 expression and caused a significant reduction in airway hyper-responsiveness (AHR) in Cre-inducible mice. These findings suggest that βarr2 is actively required for perpetuation of the AHR component of the allergic asthma phenotype. Our finding that βarr2 participates in the perpetuation of AHR in an asthma model means that targeting βarr2 may provide immediate and potentially long-term relief from daily asthma symptoms due to AHR irrespective of inflammation.
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Affiliation(s)
- Minyong Chen
- Departments of 1 Medicine (Gastroenterology) and
| | | | | | | | | | - Wei Chen
- Departments of 1 Medicine (Gastroenterology) and
| | - Julia K L Walker
- 2 Medicine (Pulmonary), and.,3 Duke University School of Nursing, Duke University Medical Center, Durham, North Carolina
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24
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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25
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Tseng HC, Arasteh A, Kaur K, Kozlowska A, Topchyan P, Jewett A. Differential Cytotoxicity but Augmented IFN-γ Secretion by NK Cells after Interaction with Monocytes from Humans, and Those from Wild Type and Myeloid-Specific COX-2 Knockout Mice. Front Immunol 2015; 6:259. [PMID: 26106386 PMCID: PMC4460808 DOI: 10.3389/fimmu.2015.00259] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 05/11/2015] [Indexed: 12/25/2022] Open
Abstract
The list of genes, which augment NK cell function when knocked out in neighboring cells is increasing, and may point to the fundamental function of NK cells targeting cells with diminished capability to differentiate optimally since NK cells are able to target less differentiated cells, and aid in their differentiation. In this paper, we aimed at understanding the effect of monocytes from targeted knockout of COX-2 in myeloid cells (Cox-2flox/flox;LysMCre/+) and from control littermates (Cox-2flox/flox;LysM+/+) on ex vivo function of NK cells. Furthermore, we compared the effect of monocytes treated with and without lipopolysaccharide (LPS) on NK cells from mice and humans. NK cells purified from Cox-2flox/flox;LysMCre/+ mice had heightened cytotoxic activity when compared to those obtained from control littermates. In addition, NK cells cultured with autologous Cox-2flox/flox;LysMCre/+ monocytes and DCs, mouse embryonic fibroblasts from global knockout COX-2, but not with knockout of COX-2 in T cells, had increased cytotoxic function as well as augmented IFN-γ secretion when compared to NK cells from control littermates cultured with monocytes. LPS inhibited NK cell cytotoxicity while increasing IFN-γ secretion when cultured in the presence of monocytes from either Cox-2flox/flox;LysMCre/+ or control littermates. In contrast to mice, NK cells from humans when cultured with monocytes lost cytotoxic function and gained ability to secrete large amounts of IFN-γ, a process, which we had previously coined as “split anergy.” Similar to mice, LPS potentiated the loss of human NK cell cytotoxicity while increasing IFN-γ secretion in the presence of monocytes. Greater loss of cytotoxicity and larger secretion of IFN-γ in NK cells induced by gene knockout cells may be important for the greater need of these cells for differentiation.
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Affiliation(s)
- Han-Ching Tseng
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA
| | - Aida Arasteh
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA
| | - Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA
| | - Anna Kozlowska
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA ; Department of Tumor Immunology, Poznan University of Medical Sciences , Poznan , Poland
| | - Paytsar Topchyan
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA ; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine , Los Angeles, CA , USA
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26
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Leslie CC. Cytosolic phospholipase A₂: physiological function and role in disease. J Lipid Res 2015; 56:1386-402. [PMID: 25838312 DOI: 10.1194/jlr.r057588] [Citation(s) in RCA: 298] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Indexed: 02/06/2023] Open
Abstract
The group IV phospholipase A2 (PLA2) family is comprised of six intracellular enzymes (GIVA, -B, -C, -D, -E, and -F) commonly referred to as cytosolic PLA2 (cPLA2)α, -β, -γ, -δ, -ε, and -ζ. They contain a Ser-Asp catalytic dyad and all except cPLA2γ have a C2 domain, but differences in their catalytic activities and subcellular localization suggest unique regulation and function. With the exception of cPLA2α, the focus of this review, little is known about the in vivo function of group IV enzymes. cPLA2α catalyzes the hydrolysis of phospholipids to arachidonic acid and lysophospholipids that are precursors of numerous bioactive lipids. The regulation of cPLA2α is complex, involving transcriptional and posttranslational processes, particularly increases in calcium and phosphorylation. cPLA2α is a highly conserved widely expressed enzyme that promotes lipid mediator production in human and rodent cells from a variety of tissues. The diverse bioactive lipids produced as a result of cPLA2α activation regulate normal physiological processes and disease pathogenesis in many organ systems, as shown using cPLA2α KO mice. However, humans recently identified with cPLA2α deficiency exhibit more pronounced effects on health than observed in mice lacking cPLA2α, indicating that much remains to be learned about this interesting enzyme.
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Affiliation(s)
- Christina C Leslie
- Department of Pediatrics, National Jewish Health, Denver, CO 80206; and Departments of Pathology and Pharmacology, University of Colorado Denver, Aurora, CO 80045
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27
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Norimoto A, Hirose K, Iwata A, Tamachi T, Yokota M, Takahashi K, Saijo S, Iwakura Y, Nakajima H. Dectin-2 promotes house dust mite-induced T helper type 2 and type 17 cell differentiation and allergic airway inflammation in mice. Am J Respir Cell Mol Biol 2014; 51:201-9. [PMID: 24588637 DOI: 10.1165/rcmb.2013-0522oc] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The fact that sensitization against fungi is closely related to the severity of asthma suggests that immune systems recognizing fungi are involved in the pathogenesis of severe asthma. Recently, Dectin-2 (gene symbol, Clec4n), a C-type lectin receptor, has been shown to function as not only a major pattern-recognition receptor for fungi, but also a receptor for some components of house dust mite (HDM) extract, a major allergen for asthma. However, the roles of Dectin-2 in the induction of HDM-induced allergic airway inflammation remain largely unknown. Our objective was to determine the roles of Dectin-2 in HDM-induced allergic airway inflammation. We examined the roles of Dectin-2 in the induction of HDM-induced T helper (Th) 2 and Th17 cell differentiation and subsequent allergic airway inflammation by using Clec4n-deficient (Clec4n(-/-)) mice. We also investigated Dectin-2-expressing cells in the lung and their roles in HDM-induced allergic airway inflammation. Clec4n(-/-) mice showed significantly attenuated HDM-induced allergic airway inflammation and decreased Th2 and Th17 cell differentiation. Dectin-2 mRNA, together with Dectin-3 and Fc receptor-γ mRNAs, was expressed in CD11b(+) dendritic cells (DCs), but not in CD4(+) T cells or epithelial cells in the lung. CD11b(+) DCs isolated from Clec4n(-/-) mice expressed lower amounts of proinflammatory cytokines and costimulatory molecules, which could lead to Th2 and Th17 cell differentiation than those from wild-type mice. HDM-pulsed Clec4n(-/-) DCs were less efficient for the induction of allergic airway inflammation than HDM-pulsed wild-type DCs. In conclusion, Dectin-2 expressed on CD11b(+) DCs promotes HDM-induced Th2 and Th17 cell differentiation and allergic airway inflammation.
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Affiliation(s)
- Ayako Norimoto
- 1 Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
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28
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Zhou W, Goleniewska K, Zhang J, Dulek DE, Toki S, Lotz MT, Newcomb DC, Boswell MG, Polosukhin VV, Milne GL, Wu P, Moore ML, FitzGerald GA, Peebles RS. Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling. J Allergy Clin Immunol 2014; 134:698-705.e5. [PMID: 25042746 DOI: 10.1016/j.jaci.2014.06.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 05/07/2014] [Accepted: 06/06/2014] [Indexed: 01/20/2023]
Abstract
BACKGROUND The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known. OBJECTIVE To determine the role of the COX pathway and prostaglandin I2 (PGI2) signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance. METHODS Wild-type (WT) BALB/c mice and IP knockout mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements. RESULTS WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti-tolerance effect of COX inhibition. CONCLUSION COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and that clinical use of COX-inhibiting drugs may increase the risk of developing allergic diseases.
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Affiliation(s)
- Weisong Zhou
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
| | - Kasia Goleniewska
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Jian Zhang
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Daniel E Dulek
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Shinji Toki
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Matthew T Lotz
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Dawn C Newcomb
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Madison G Boswell
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Vasiliy V Polosukhin
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Ginger L Milne
- Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Pingsheng Wu
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Martin L Moore
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga
| | | | - R Stokes Peebles
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
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29
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Shi M, Shi G, Tang J, Kong D, Bao Y, Xiao B, Zuo C, Wang T, Wang Q, Shen Y, Wang H, Funk CD, Zhou J, Yu Y. Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice. J Allergy Clin Immunol 2014; 134:1163-74.e16. [PMID: 24948368 DOI: 10.1016/j.jaci.2014.04.035] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 03/06/2014] [Accepted: 04/21/2014] [Indexed: 01/17/2023]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma, but their regulation in patients with aspirin-intolerant asthma (AIA) remains unclear. OBJECTIVE We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice. METHODS Allergic airway inflammation was induced in mice by means of ovalbumin challenge. The distribution and function of MDSCs in mice were analyzed by using flow cytometry and pharmacologic/gene manipulation approaches. RESULTS CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSCs (polymorphonuclear MDSCs [PMN-MDSCs]) recruited to the lungs are negatively correlated with airway inflammation in allergen-challenged mice. Aspirin-treated and COX-1 knockout (KO) mice showed significantly lower accumulation of PMN-MDSCs in the inflamed lung and immune organs accompanied by increased TH2 airway responses. The TH2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1-derived prostaglandin E2 promoted PMN-MDSC generation in bone marrow through E prostanoid 2 and 4 receptors (EP2 and EP4), whereas the impaired arginase-1 expression in PMN-MDSCs in COX-1 KO mice was mediated by dysregulation of the prostaglandin E2/EP4/cyclic AMP/protein kinase A pathway. EP4 agonist administration alleviated allergy-induced airway hyperresponsiveness in COX-1 KO mice. Moreover, the immunosuppressive function of PMN-MDSCs from patients with AIA was dramatically decreased compared with that from patients with aspirin-tolerant asthma. CONCLUSION The immunosuppressive activity of PMN-MDSCs was diminished in both allergen-challenged COX-1 KO mice and patients with AIA, probably through an EP4-mediated signaling pathway, indicating that activation of PMN-MDSCs might be a promising therapeutic strategy for asthma, particularly AIA.
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Affiliation(s)
- Maohua Shi
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Guochao Shi
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juan Tang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Deping Kong
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yao Bao
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Xiao
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Caojian Zuo
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Tai Wang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qingsong Wang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yujun Shen
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hui Wang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China
| | - Colin D Funk
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Jie Zhou
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou, China.
| | - Ying Yu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
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30
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Sayers BC, Taylor AJ, Glista-Baker EE, Shipley-Phillips JK, Dackor RT, Edin ML, Lih FB, Tomer KB, Zeldin DC, Langenbach R, Bonner JC. Role of cyclooxygenase-2 in exacerbation of allergen-induced airway remodeling by multiwalled carbon nanotubes. Am J Respir Cell Mol Biol 2014; 49:525-35. [PMID: 23642096 DOI: 10.1165/rcmb.2013-0019oc] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The emergence of nanotechnology has produced a multitude of engineered nanomaterials such as carbon nanotubes (CNTs), and concerns have been raised about their effects on human health, especially for susceptible populations such as individuals with asthma. Multiwalled CNTs (MWCNTs) have been shown to exacerbate ovalbumin (OVA)-induced airway remodeling in mice. Moreover, cyclooxygenase-2 (COX-2) has been described as a protective factor in asthma. We postulated that COX-2-deficient (COX-2(-/-)) mice would be susceptible to MWCNT-induced exacerbations of allergen-induced airway remodeling, including airway inflammation, fibrosis, and mucus-cell metaplasia (i.e., the formation of goblet cells). Wild-type (WT) or COX-2(-/-) mice were sensitized to OVA to induce allergic airway inflammation before a single dose of MWCNTs (4 mg/kg) delivered to the lungs by oropharyngeal aspiration. MWCNTs significantly increased OVA-induced lung inflammation and mucus-cell metaplasia in COX-2(-/-) mice compared with WT mice. However, airway fibrosis after exposure to allergen and MWCNTs was no different between WT and COX-2(-/-) mice. Concentrations of certain prostanoids (prostaglandin D2 and thromboxane B2) were enhanced by OVA or MWCNTs in COX-2(-/-) mice. No differences in COX-1 mRNA concentrations were evident between WT and COX-2(-/-) mice treated with OVA and MWCNTs. Interestingly, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13 and IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2(-/-) mice, but not in WT mice. We conclude that exacerbations of allergen-induced airway inflammation and mucus-cell metaplasia by MWCNTs are enhanced by deficiencies in COX-2, and are associated with the activation of a mixed Th1/Th2/Th17 immune response.
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Affiliation(s)
- Brian C Sayers
- 1 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina
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Zasłona Z, Okunishi K, Bourdonnay E, Domingo-Gonzalez R, Moore BB, Lukacs NW, Aronoff DM, Peters-Golden M. Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. J Allergy Clin Immunol 2014; 133:379-87. [PMID: 24075232 PMCID: PMC3960315 DOI: 10.1016/j.jaci.2013.07.037] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 07/24/2013] [Accepted: 07/31/2013] [Indexed: 01/09/2023]
Abstract
BACKGROUND Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E₂ or of specific E prostanoid (EP) receptors is not known. OBJECTIVE Here we tested the role of EP2 signaling in allergic asthma. METHODS Wild-type (WT) and EP2(-/-) mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2(-/-) CD4 T cells was used to validate the importance of EP2 expression on T cells. RESULTS Compared with WT mice, EP2(-/-) mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2(-/-) mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2(-/-) mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE₂ decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28-stimulated CD4(+) T cells. Coculture of flow cytometry-sorted splenic CD4(+) T cells and CD11c(+) dendritic cells from WT or EP2(-/-) mice suggested that the increased IL-13 production in EP2(-/-) mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4(+) EP2(-/-) T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4(+) T cells. CONCLUSION We conclude that the PGE2-EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma.
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Affiliation(s)
- Zbigniew Zasłona
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich
| | - Katsuhide Okunishi
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich
| | - Emilie Bourdonnay
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich
| | - Racquel Domingo-Gonzalez
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich
| | - Bethany B Moore
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich
| | - Nicholas W Lukacs
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich
| | - David M Aronoff
- Division of Infectious Disease, University of Michigan Medical School, Ann Arbor, Mich
| | - Marc Peters-Golden
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich.
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Iwata A, Kawashima S, Kobayashi M, Okubo A, Kawashima H, Suto A, Hirose K, Nakayama T, Nakajima H. Th2-type inflammation instructs inflammatory dendritic cells to induce airway hyperreactivity. Int Immunol 2013; 26:103-14. [PMID: 24150243 DOI: 10.1093/intimm/dxt047] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Dendritic cells (DCs) play critical roles in determining the fate of CD4⁺ T cells. Among DC sub-populations, monocyte-derived inflammatory DCs (iDCs) have been shown to play an important role in the induction of adaptive immune responses under inflammatory conditions. Although previous studies have shown that DCs have an indispensable role in the induction of allergic airway inflammation and airway hyperreactivity (AHR) in murine asthma models, the precise roles of iDCs in the asthmatic responses remain largely unknown. We show here that T(h)2 cell-mediated inflammation in murine asthma models induces the expression of some markers of alternatively activated macrophage such as arginase 1 and resistin-like molecule-α in iDCs by a mechanism depending on the intrinsic expression of STAT6. In contrast, T(h)1 cell-mediated inflammation induces iDCs to express TNF-α and inducible nitric oxide synthase (iNOS), markers of TNF-α- and iNOS-producing DCs. Moreover, we show that iDCs under a T(h)2 environment play an important role in the induction of AHR, independently of allergic airway inflammation. Our results thus indicate the importance of iDCs in the induction of AHR as downstream effector cells in T(h)2 cell-mediated asthmatic responses.
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Donovan C, Royce SG, Esposito J, Tran J, Ibrahim ZA, Tang MLK, Bailey S, Bourke JE. Differential effects of allergen challenge on large and small airway reactivity in mice. PLoS One 2013; 8:e74101. [PMID: 24040180 PMCID: PMC3765301 DOI: 10.1371/journal.pone.0074101] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 07/30/2013] [Indexed: 01/21/2023] Open
Abstract
The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways disease to induce inflammation and remodelling and determine whether in vivo hyperresponsiveness to methacholine is consistent with in vitro reactivity of trachea and small airways. Balb/C mice were sensitised (days 0, 14) and challenged (3 times/week, 6 weeks) with ovalbumin. Airway reactivity was compared with saline-challenged controls in vivo assessing whole lung resistance, and in vitro measuring the force of tracheal contraction and the magnitude/rate of small airway narrowing within lung slices. Increased airway inflammation, epithelial remodelling and fibrosis were evident following allergen challenge. In vivo hyperresponsiveness to methacholine was maintained in isolated trachea. In contrast, methacholine induced slower narrowing, with reduced potency in small airways compared to controls. In vitro incubation with IL-1/TNFα did not alter reactivity. The hyporesponsiveness to methacholine in small airways within lung slices following chronic ovalbumin challenge was unexpected, given hyperresponsiveness to the same agonist both in vivo and in vitro in tracheal preparations. This finding may reflect the altered interactions of small airways with surrounding parenchymal tissue after allergen challenge to oppose airway narrowing and closure.
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Affiliation(s)
- Chantal Donovan
- Lung Health Research Centre, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia
| | - Simon G. Royce
- Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia
- Department of Allergy & Immunology, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
| | - James Esposito
- Lung Health Research Centre, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia
| | - Jenny Tran
- Lung Health Research Centre, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia
| | - Zaridatul Aini Ibrahim
- Lung Health Research Centre, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia
| | - Mimi L. K. Tang
- Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia
- Department of Allergy & Immunology, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
| | - Simon Bailey
- Lung Health Research Centre, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia
- Faculty of Veterinary Science, University of Melbourne, Parkville, Victoria, Australia
| | - Jane E. Bourke
- Lung Health Research Centre, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia
- * E-mail:
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Boyce JA, Peebles RS. Regulation of Th9-type pulmonary immune responses: a new role for COX-2. Am J Respir Crit Care Med 2013; 187:785-6. [PMID: 23586375 DOI: 10.1164/rccm.201302-0205ed] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Li H, Edin ML, Bradbury JA, Graves JP, DeGraff LM, Gruzdev A, Cheng J, Dackor RT, Wang PM, Bortner CD, Garantziotis S, Jetten AM, Zeldin DC. Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB. Am J Respir Crit Care Med 2013; 187:812-22. [PMID: 23449692 DOI: 10.1164/rccm.201211-2073oc] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
RATIONALE Helper CD4(+) T cell subsets, including IL-9- and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation. OBJECTIVES To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation. METHODS COX-1(-/-), COX-2(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. MEASUREMENTS AND MAIN RESULTS Experimental endpoints were not different between COX-1(-/-) and WT mice; however, the percentage of IL-9(+) CD4(+) T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2(-/-) mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD2 and PGE2, which also reduced Th9 cell differentiation of murine and human naive CD4(+) T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4(+) T cells isolated from WT mice in vitro. CONCLUSIONS COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.
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Affiliation(s)
- Hong Li
- Laboratory of Respiratory Biology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 2013; 138:485-502. [PMID: 23523686 PMCID: PMC3661976 DOI: 10.1016/j.pharmthera.2013.03.006] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 03/07/2013] [Indexed: 01/06/2023]
Abstract
The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists.
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Key Words
- ampk, amp-activated protein kinase
- camp, cyclic adenylyl monophosphate
- cftr, cystic fibrosis transmembrane conductance regulator
- clc, chloride channel
- cox, cyclooxygenase
- creb, camp-response element-binding protein
- dp, d-type prostanoid receptor
- dss, dextran sodium sulfate
- egfr, epidermal growth factor receptor
- enos, endothelial nitric oxide synthase
- ep, e-type prostanoid receptor
- epac, exchange protein activated by camp
- eprap, ep4 receptor-associated protein
- erk, extracellular signal-regulated kinase
- fem1a, feminization 1 homolog a
- fp, f-type prostanoid receptor
- grk, g protein-coupled receptor kinase
- 5-hete, 5-hydroxyeicosatetraenoic acid
- icer, inducible camp early repressor
- icam-1, intercellular adhesion molecule-1
- ig, immunoglobulin
- il, interleukin
- ifn, interferon
- ip, i-type prostanoid receptor
- lps, lipopolysaccharide
- map, mitogen-activated protein kinase
- mcp, monocyte chemoattractant protein
- mek, map kinase kinase
- nf-κb, nuclear factor kappa-light-chain-enhancer of activated b cells
- nsaid, non-steroidal anti-inflammatory drug
- pg, prostaglandin
- pi3k, phosphatidyl insositol 3-kinase
- pk, protein kinase
- tp, t-type prostanoid receptor
- tx, thromboxane receptor
- prostaglandins
- inflammation
- vascular disease
- cancerogenesis
- renal function
- osteoporosis
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Affiliation(s)
| | | | | | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria
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Sharma P, Ryu MH, Basu S, Maltby SA, Yeganeh B, Mutawe MM, Mitchell RW, Halayko AJ. Epithelium-dependent modulation of responsiveness of airways from caveolin-1 knockout mice is mediated through cyclooxygenase-2 and 5-lipoxygenase. Br J Pharmacol 2013; 167:548-60. [PMID: 22551156 DOI: 10.1111/j.1476-5381.2012.02014.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Acute silencing of caveolin-1 (Cav-1) modulates receptor-mediated contraction of airway smooth muscle. Moreover, COX-2- and 5-lipoxygenase (5-LO)-derived prostaglandin and leukotriene biosynthesis can influence smooth muscle reactivity. COX-2 half-life can be prolonged through association with Cav-1. We suggested that lack of Cav-1 modulated levels of COX-2 which in turn modulated tracheal contraction, when arachidonic acid signalling was disturbed by inhibition of COX-2. EXPERIMENTAL APPROACH Using tracheal rings from Cav-1 knockout (KO) and wild-type mice (B6129SF2/J), we measured isometric contractions to methacholine and used PCR, immunoblotting and immunohistology to monitor expression of relevant proteins. KEY RESULTS Tracheal rings from Cav-1 KO and wild-type mice exhibited similar responses, but the COX-2 inhibitor, indomethacin, increased responses of tracheal rings from Cav-1 KO mice to methacholine. The phospholipase A₂ inhibitor, eicosatetraynoic acid, which inhibits formation of both COX-2 and 5-LO metabolites, had no effect on wild-type or Cav-1 KO tissues. Indomethacin-mediated hyperreactivity was ablated by the LTD₄ receptor antagonist (montelukast) and 5-LO inhibitor (zileuton). The potentiating effect of indomethacin on Cav-1 KO responses to methacholine was blocked by epithelial denudation. Immunoprecipitation showed that COX-2 binds Cav-1 in wild-type lungs. Immunoblotting and qPCR revealed elevated levels of COX-2 and 5-LO protein, but not COX-1, in Cav-1 KO tracheas, a feature that was prevented by removal of the epithelium. CONCLUSION AND IMPLICATIONS The indomethacin-induced hypercontractility observed in Cav-1 KO tracheas was linked to increased expression of COX-2 and 5-LO, which probably enhanced arachidonic acid shunting and generation of pro-contractile leukotrienes when COX-2 was inhibited.
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Affiliation(s)
- Pawan Sharma
- Department of Physiology, University of Manitoba, Winnipeg, MB, Canada
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Serra-Pages M, Olivera A, Torres R, Picado C, de Mora F, Rivera J. E-prostanoid 2 receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling. J Leukoc Biol 2012; 92:1155-65. [PMID: 22859831 PMCID: PMC3501892 DOI: 10.1189/jlb.0212109] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Revised: 07/17/2012] [Accepted: 07/18/2012] [Indexed: 01/11/2023] Open
Abstract
The experimental administration of PGE(2) for the treatment of asthma dampens clinical symptoms, and similar efficacy has been found in dust mite-induced hypersensitivity reactions in animal models. Here, we investigate the mechanism by which PGE(2) mediates suppression of MC degranulation. We find that the effect of PGE(2) on FcεRI-dependent MC degranulation varies from activating to suppressing, depending on the relative ratio of EP(2) to EP(3) expression on these cells with suppression evident only in cells having increased EP(2) to EP(3) expression. Consistent with a role for EP(2) in suppressing MC responses in vitro, we found that a selective EP(2) agonist, Butaprost, inhibited MC-mediated FcεRI-induced immediate hypersensitivity in a model of PCA. EP(2) engagement on MCs increased cAMP production and inhibited FcεRI-mediated calcium influx. In addition, it also decreased the extent of FcεRI-induced Fyn kinase activity, leading to decreased phosphorylation of key signaling molecules such as Gab2 and Akt. Treatment with an antagonist of cAMP or shRNA down-regulation of PKA (the principal intracellular target of cAMP) reversed the EP(2)-mediated inhibitory effect on MC degranulation and restored calcium influx and phosphorylation of Akt. Collectively, the findings demonstrate that EP(2) suppresses the Fyn-mediated signals that are central to FcεRI-dependent MC degranulation, suggesting that engagement of the EP(2) on MCs may be beneficial in dampening allergic responses.
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MESH Headings
- Alprostadil/analogs & derivatives
- Alprostadil/pharmacology
- Animals
- Calcium/metabolism
- Cell Degranulation/drug effects
- Cell Degranulation/genetics
- Cell Degranulation/immunology
- Cell Line
- Cells, Cultured
- Cyclic AMP/metabolism
- Cyclic AMP-Dependent Protein Kinases/genetics
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Dinoprostone/pharmacology
- Female
- Gene Silencing
- Humans
- Immunoglobulin E/immunology
- Immunoglobulin E/metabolism
- Mast Cells/drug effects
- Mast Cells/immunology
- Mast Cells/metabolism
- Mice
- Proto-Oncogene Proteins c-fyn/metabolism
- Receptors, Prostaglandin E, EP2 Subtype/agonists
- Receptors, Prostaglandin E, EP2 Subtype/genetics
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP3 Subtype/agonists
- Receptors, Prostaglandin E, EP3 Subtype/genetics
- Receptors, Prostaglandin E, EP3 Subtype/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Mariona Serra-Pages
- Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain; and
| | - Ana Olivera
- Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Rosa Torres
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain; and
- Department of Pneumology and Respiratory Allergy, Hospital Clínic i Universitari de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
| | - César Picado
- Department of Pneumology and Respiratory Allergy, Hospital Clínic i Universitari de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
| | - Fernando de Mora
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain; and
| | - Juan Rivera
- Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Piret SE, Esapa CT, Gorvin CM, Head R, Loh NY, Devuyst O, Thomas G, Brown SDM, Brown M, Croucher P, Cox R, Thakker RV. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation. PLoS One 2012; 7:e45217. [PMID: 23024809 PMCID: PMC3443222 DOI: 10.1371/journal.pone.0045217] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Accepted: 08/14/2012] [Indexed: 11/27/2022] Open
Abstract
Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid.
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Affiliation(s)
- Sian E. Piret
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Christopher T. Esapa
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, United Kingdom
| | - Caroline M. Gorvin
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Rosie Head
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, United Kingdom
| | - Nellie Y. Loh
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Olivier Devuyst
- Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Gethin Thomas
- The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Steve D. M. Brown
- Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, United Kingdom
| | - Matthew Brown
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Peter Croucher
- Garvan Institute for Medical Research, Sydney, Australia
| | - Roger Cox
- Mammalian Genetics Unit, MRC Harwell, Harwell Science and Innovation Campus, United Kingdom
| | - Rajesh V. Thakker
- Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
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Yildirim E, Carey MA, Card JW, Dietrich A, Flake GP, Zhang Y, Bradbury JA, Rebolloso Y, Germolec DR, Morgan DL, Zeldin DC, Birnbaumer L. Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice. Am J Physiol Lung Cell Mol Physiol 2012; 303:L539-49. [PMID: 22797250 DOI: 10.1152/ajplung.00389.2011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca²⁺ entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca²⁺ signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient (Trpc1(-/-)) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1(-/-) splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1(-/-) mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.
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Affiliation(s)
- Eda Yildirim
- Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA
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Malhotra S, Deshmukh SS, Dastidar SG. COX inhibitors for airway inflammation. Expert Opin Ther Targets 2012; 16:195-207. [PMID: 22324934 DOI: 10.1517/14728222.2012.661416] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION The cyclooxygenase (COX) enzyme, which is responsible for the production of prostaglandins (PGs), key mediators of inflammation, may have the potential to become an attractive target for anti-inflammatory therapy. COX catalyzes the conversion of arachidonic acid (AA) into PGs, which play a significant role in disease. PGs are lipid mediators of central importance in the regulation of inflammation and smooth muscle tone. Airway-resident inflammatory cells release PGs: PGD2 and PDF2a amplify smooth muscle contraction and airway inflammation. Following its conversion from membrane phospholipids by phospholipase, AA enters the prostanoid pathway via COX, which catalyzes the conversion of AA to PGH2. PGH2 is then converted to biologically active PGs by cell-specific PG synthases. As COX is the rate limiting step in the PG pathway, the regulation of this enzyme is of critical importance in PG production. AREAS COVERED This review addresses the opportunities and challenges of COX inhibitors as therapeutic targets in airway inflammation. The review covers literature from the past 20 years. EXPERT OPINION Current literature favors COX inhibitors as potential targets for airway diseases. However, from the information available, it is not clear whether the COX enzyme by itself can serve as a target in drug development for asthma and COPD. Therefore, additional research is required to elucidate the mechanisms of action of COX metabolites before it can be considered as a target.
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Affiliation(s)
- Sanjay Malhotra
- Daiichi Sankyo India Pharma Private Ltd., Department of Chemistry, Haryana, India.
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Lee JK, Sayers BC, Chun KS, Lao HC, Shipley-Phillips JK, Bonner JC, Langenbach R. Multi-walled carbon nanotubes induce COX-2 and iNOS expression via MAP kinase-dependent and -independent mechanisms in mouse RAW264.7 macrophages. Part Fibre Toxicol 2012; 9:14. [PMID: 22571318 PMCID: PMC3485091 DOI: 10.1186/1743-8977-9-14] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 05/09/2012] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Carbon nanotubes (CNTs) are engineered graphene cylinders with numerous applications in engineering, electronics and medicine. However, CNTs cause inflammation and fibrosis in the rodent lung, suggesting a potential human health risk. We hypothesized that multi-walled CNTs (MWCNTs) induce two key inflammatory enzymes in macrophages, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), through activation of extracellular signal-regulated kinases (ERK1,2). METHODS RAW264.7 macrophages were exposed to MWCNTs or carbon black nanoparticles (CBNPs) over a range of doses and time course. Uptake and subcellular localization of MWCNTs was visualized by transmission electron microscopy (TEM). Protein levels of COX-2, iNOS, and ERK1,2 (total ERK and phosphorylated ERK) were measured by Western blot analysis. Prostaglandin-E(2) (PGE(2)) and nitric oxide (NO) levels in cell supernatants were measured by ELISA and Greiss assay, respectively. RESULTS MWCNTs, but not CBNPs, induced COX-2 and iNOS in a time- and dose-dependent manner. COX-2 and iNOS induction by MWCNTs correlated with increased PGE(2) and NO production, respectively. MWCNTs caused ERK1,2 activation and inhibition of ERK1,2 (U0126) blocked MWCNT induction of COX-2 and PGE2 production, but did not reduce the induction of iNOS. Inhibition of iNOS (L-NAME) did not affect ERK1,2 activation, nor did L-NAME significantly decrease COX-2 induction by MWCNT. Nickel nanoparticles (NiNPs), which are present in MWCNTs as a residual catalyst, also induced COX-2 via ERK-1,2. However, a comparison of COX-2 induction by MWCNTs containing 4.5 and 1.8% Ni did not show a significant difference in ability to induce COX-2, indicating that characteristics of MWCNTs in addition to Ni content contribute to COX-2 induction. CONCLUSION This study identifies COX-2 and subsequent PGE(2) production, along with iNOS induction and NO production, as inflammatory mediators involved in the macrophage response to MWCNTs. Furthermore, our work demonstrates that COX-2 induction by MWCNTs in RAW264.7 macrophages is ERK1,2-dependent, while iNOS induction by MWCNTs is ERK1,2-independent. Our data also suggest contributory physicochemical factors other than residual Ni catalyst play a role in COX-2 induction to MWCNT.
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Affiliation(s)
- Jong Kwon Lee
- Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
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Abstract
Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to an increased risk of tumorigenesis and tumor cell invasiveness. Various bioactive lipids, particularly those formed by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, have been well established as therapeutic targets for many epithelial cancers. Emerging studies suggest that there is a role for anti-inflammatory bioactive lipids and their mediators during the resolution phase of inflammation. These proresolving bioactive lipids, including lipoxins (LXs) and resolvins (RVs), have potent anti-inflammatory and anti-carcinogenic properties. The molecular signaling pathways controlling generation and degradation of the proresolving mediators LXs and RVs are now being elucidated, and the component molecules may serve as new targets for regulation of inflammation and inflammation-associated cancers like colon and pancreatic cancers. This review will highlight the recent advances in our understanding of how these bioactive lipids and proresolving mediators may function with various immune cells and cytokines in inhibiting tumor cell proliferation and progression and invasiveness of colon and pancreatic cancers.
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Westover AJ, Hooper SB, Wallace MJ, Moss TJM. Prostaglandins mediate the fetal pulmonary response to intrauterine inflammation. Am J Physiol Lung Cell Mol Physiol 2012; 302:L664-78. [DOI: 10.1152/ajplung.00297.2011] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Intra-amniotic (IA) lipopolysaccharide (LPS) induces intrauterine and fetal lung inflammation and increases lung surfactant and compliance in preterm sheep; however, the mechanisms are unknown. Prostaglandins (PGs) are inflammatory mediators, and PGE2 has established roles in fetal lung surfactant production. The aim of our first study was to determine PGE2 concentrations in response to IA LPS and pulmonary gene expression for PG synthetic [prostaglandin H synthase-2 (PGHS-2) and PGE synthase (PGES)] and PG-metabolizing [prostaglandin dehydrogenase (PGDH)] enzymes and PGE2 receptors. Our second study aimed to block LPS-induced increases in PGE2 with a PGHS-2 inhibitor (nimesulide) and determine lung inflammation and surfactant protein mRNA expression. Pregnant ewes received an IA saline or LPS injection at 118 days of gestation. In study 1, fetal plasma and amniotic fluid were sampled before and at 2, 4, 6, 12, and 24 h after injection and then daily, and fetuses were delivered 2 or 7 days later. Amniotic fluid PGE2 concentrations increased ( P < 0.05) 12 h and 3–6 days after LPS. Fetal lung PGHS-2 mRNA and PGES mRNA increased 2 ( P = 0.0084) and 7 ( P = 0.014) days after LPS, respectively. In study 2, maternal intravenous nimesulide or vehicle infusion began immediately before LPS or saline injection and continued until delivery 2 days later. Nimesulide inhibited LPS-induced increases in PGE2 and decreased fetal lung IL-1β and IL-8 mRNA ( P ≤ 0.002) without altering lung inflammatory cell infiltration. Nimesulide decreased surfactant protein (SP)-A ( P = 0.05), -B ( P = 0.05), and -D ( P = 0.0015) but increased SP-C mRNA ( P = 0.023). Thus PGHS-2 mediates, at least in part, fetal pulmonary responses to inflammation.
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Affiliation(s)
| | - Stuart B. Hooper
- Ritchie Centre, Monash Institute of Medical Research and
- Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Megan J. Wallace
- Ritchie Centre, Monash Institute of Medical Research and
- Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Timothy J. M. Moss
- Ritchie Centre, Monash Institute of Medical Research and
- Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
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Church RJ, Jania LA, Koller BH. Prostaglandin E(2) produced by the lung augments the effector phase of allergic inflammation. THE JOURNAL OF IMMUNOLOGY 2012; 188:4093-102. [PMID: 22412193 DOI: 10.4049/jimmunol.1101873] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Elevated PGE(2) is a hallmark of most inflammatory lesions. This lipid mediator can induce the cardinal signs of inflammation, and the beneficial actions of nonsteroidal anti-inflammatory drugs are attributed to inhibition of cyclooxygenase (COX)-1 and COX-2, enzymes essential in the biosynthesis of PGE(2) from arachidonic acid. However, both clinical studies and rodent models suggest that, in the asthmatic lung, PGE(2) acts to restrain the immune response and limit physiological change secondary to inflammation. To directly address the role of PGE(2) in the lung, we examined the development of disease in mice lacking microsomal PGE(2) synthase-1 (mPGES1), which converts COX-1/COX-2-derived PGH(2) to PGE(2). We show that mPGES1 determines PGE(2) levels in the naive lung and is required for increases in PGE(2) after OVA-induced allergy. Although loss of either COX-1 or COX-2 increases the disease severity, surprisingly, mPGES1(-/-) mice show reduced inflammation. However, an increase in serum IgE is still observed in the mPGES1(-/-) mice, suggesting that loss of PGE(2) does not impair induction of a Th2 response. Furthermore, mPGES1(-/-) mice expressing a transgenic OVA-specific TCR are also protected, indicating that PGE(2) acts primarily after challenge with inhaled Ag. PGE(2) produced by the lung plays the critical role in this response, as loss of lung mPGES1 is sufficient to protect against disease. Together, this supports a model in which mPGES1-dependent PGE(2) produced by populations of cells native to the lung contributes to the effector phase of some allergic responses.
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Affiliation(s)
- Rachel J Church
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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He C, Wu Y, Lai Y, Cai Z, Liu Y, Lai L. Dynamic eicosanoid responses upon different inhibitor and combination treatments on the arachidonic acid metabolic network. MOLECULAR BIOSYSTEMS 2012; 8:1585-94. [DOI: 10.1039/c2mb05503a] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Luschnig-Schratl P, Sturm EM, Konya V, Philipose S, Marsche G, Fröhlich E, Samberger C, Lang-Loidolt D, Gattenlöhner S, Lippe IT, Peskar BA, Schuligoi R, Heinemann A. EP4 receptor stimulation down-regulates human eosinophil function. Cell Mol Life Sci 2011; 68:3573-87. [PMID: 21365278 PMCID: PMC3192285 DOI: 10.1007/s00018-011-0642-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Revised: 02/07/2011] [Accepted: 02/15/2011] [Indexed: 01/08/2023]
Abstract
Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE(2) receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca(2+) mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE(2) and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases.
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Affiliation(s)
- Petra Luschnig-Schratl
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Eva M. Sturm
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Viktoria Konya
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Sonia Philipose
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Gunther Marsche
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Eleonore Fröhlich
- Center for Medical Research, Medical University of Graz, Graz, Austria
| | - Claudia Samberger
- Center for Medical Research, Medical University of Graz, Graz, Austria
| | - Doris Lang-Loidolt
- Department of Otorhinolaryngology, Medical University of Graz, Graz, Austria
| | | | - Irmgard Th. Lippe
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Bernhard A. Peskar
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Rufina Schuligoi
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
| | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria
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Takahashi K, Hirose K, Kawashima S, Niwa Y, Wakashin H, Iwata A, Tokoyoda K, Renauld JC, Iwamoto I, Nakayama T, Nakajima H. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J Allergy Clin Immunol 2011; 128:1067-76.e1-6. [PMID: 21794904 DOI: 10.1016/j.jaci.2011.06.018] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Revised: 05/02/2011] [Accepted: 06/20/2011] [Indexed: 01/11/2023]
Abstract
BACKGROUND IL-22 functions as both a proinflammatory cytokine and an anti-inflammatory cytokine in various inflammations, depending on the cellular and cytokine milieu. However, the roles of IL-22 in the regulation of allergic airway inflammation are still largely unknown. OBJECTIVE We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. METHODS We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration, on antigen-induced airway inflammation. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). RESULTS Antigen inhalation induced IL-22 production in the airways of sensitized mice. CD4(+) T cells, but not other lymphocytes or innate cells, infiltrating in the airways produced IL-22, and one third of IL-22-producing CD4(+) T cells also produced IL-17A. The neutralization of IL-22 by anti-IL-22 antibody enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of recombinant IL-22 attenuated antigen-induced eosinophil recruitment into the airways. Moreover, anti-IL-22 antibody enhanced antigen-induced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on antigen-induced eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1β- or LPS-stimulated MLE-15 cells. CONCLUSION IL-22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells.
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Affiliation(s)
- Kentaro Takahashi
- Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan
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Stumm CL, Wettlaufer SH, Jancar S, Peters-Golden M. Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2011; 301:L636-44. [PMID: 21873451 DOI: 10.1152/ajplung.00158.2011] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E(2) (PGE(2)) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE(2) synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE(2) axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of PGE(2) or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP(2) receptor, which is pivotal for PGE(2) responsiveness. However, cytokine-induced upregulation of PGE(2) biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX-2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE(2) acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE(2) generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma.
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Affiliation(s)
- Camila Leindecker Stumm
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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50
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Li H, Bradbury JA, Dackor RT, Edin ML, Graves JP, DeGraff LM, Wang PM, Bortner CD, Maruoka S, Lih FB, Cook DN, Tomer KB, Jetten AM, Zeldin DC. Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation. Am J Respir Crit Care Med 2011; 184:37-49. [PMID: 21474648 PMCID: PMC3172888 DOI: 10.1164/rccm.201010-1637oc] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Accepted: 04/07/2011] [Indexed: 01/15/2023] Open
Abstract
RATIONALE Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation. OBJECTIVES To determine the role of COX metabolites in regulating Th17 cell differentiation and function during allergic lung inflammation. METHODS COX-1(-/-), COX-2(-/-), and wild-type mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th17 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time polymerase chain reaction, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. MEASUREMENTS AND MAIN RESULTS Th17 cell differentiation in lung, lymph nodes, and bronchoalveolar lavage fluid was significantly lower in COX-2(-/-) mice after ovalbumin sensitization and exposure in vivo. In vitro studies revealed significantly impaired Th17 cell differentiation of COX-2(-/-) naive CD4(+) T cells with decreased Stat3 phosphorylation and RORγt expression. Synthetic PGF(2α) and PGI(2) enhanced Th17 cell differentiation of COX-2(-/-) CD4(+) T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF(2α) receptor and PGI(2) receptor siRNA knockdown significantly decreased Th17 cell differentiation in vitro. Administration of synthetic PGs restored accumulation of Th17 cells in lungs of allergic COX-2(-/-) mice in vivo. CONCLUSIONS COX-2 is a critical regulator of Th17 cell differentiation during allergic lung inflammation via autocrine signaling of PGI(2) and PGF(2α) through their respective cell surface receptors.
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Affiliation(s)
- Hong Li
- Laboratories of Respiratory Biology
| | | | | | | | | | | | | | | | | | - Fred B. Lih
- Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | | | - Kenneth B. Tomer
- Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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