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Jin M, Komine M, Tsuda H, Sashikawa-Kimura M, Nakae S, Motegi SI, Ohtsuki M. Interleukin-33 Deficiency Protects the Skin From Ulcer Formation in an Ischemia-Reperfusion-Induced Decubitus Mouse Model. Exp Dermatol 2024; 33:e70014. [PMID: 39555678 DOI: 10.1111/exd.70014] [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: 06/04/2024] [Revised: 10/14/2024] [Accepted: 10/25/2024] [Indexed: 11/19/2024]
Abstract
Interleukin-33 (IL-33) is an alarmin released upon epithelial tissue damage. It functions as a nuclear factor for regulating gene expression. We hypothesised that IL-33 is involved in the formation of decubitus ulcers through damaged epidermis. Therefore, this study aimed to clarify the mechanism of IL-33 action in decubitus ulcer formation. IL-33 knockout (KO), soluble stimulation-2 (ST2) transgenic, and wild-type (WT) mice were used to construct an ischemia-reperfusion (I/R) injury as a decubitus model. The ulcer area was significantly reduced in IL-33 KO mice compared to WT mice but was not reduced in ST2 transgenic mice. Anti-IL-33 receptor (transmembrane ST2) antibodies effectively prevented ulcer formation; however, an anti-IL-33 neutralising antibody was ineffective. The number of infiltrating macrophages was higher, while that of neutrophils and mast cells was lower in IL-33 KO mice than in WT mice. The number of M2 macrophages increased in IL-33 KO mice. Characterisation of gene expression levels revealed significantly reduced interleukin-1 beta (IL-1β) and increased C-C motif chemokine ligand 17 expression in IL-33 KO mice. Macrophages isolated from ulcers in WT or IL-33 KO mice stimulated with exogenous IL-33 produced comparable amounts of IL-1β. In conclusion, our study indicates that IL-33 is released in response to I/R injury in the skin, contributing to inflammatory macrophage and mast cell infiltration and stimulation, resulting in IL-1β production and the massive infiltration of effector cells, including neutrophils, which finally induces decubitus ulcer formation. These results suggest that suppressing IL-33 expression could be beneficial for treating early-phase decubitus ulcers.
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Affiliation(s)
- Meijuan Jin
- Department of Dermatology, Jichi Medical University, Tochigi, Japan
| | - Mayumi Komine
- Department of Dermatology, Jichi Medical University, Tochigi, Japan
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
| | - Hidetoshi Tsuda
- Department of Dermatology, Jichi Medical University, Tochigi, Japan
- Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | | | - Susumu Nakae
- Graduate School of Integrated Science of Life, Hiroshima University Graduate School, Hiroshima, Japan
| | | | - Mamitaro Ohtsuki
- Department of Dermatology, Jichi Medical University, Tochigi, Japan
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Belfrage H, Kuuliala K, Kuuliala A, Mustonen H, Puolakkainen P, Kylänpää L, Louhimo J. Circulating Markers of Necroptosis in Acute Pancreatitis. Dig Dis Sci 2024; 69:3333-3343. [PMID: 38940973 PMCID: PMC11415434 DOI: 10.1007/s10620-024-08530-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 06/11/2024] [Indexed: 06/29/2024]
Abstract
OBJECTIVES Necroptosis, a programmed inflammatory cell death, is involved in the pathogenesis of acute pancreatitis (AP). We compared levels of interleukin (IL)-33 (released upon necroptosis), sST2 (soluble IL-33 receptor), MLKL, RIPK1 and RIPK3 (necroptosis executioner proteins), and proinflammatory cytokines IL-6, TNF and IL-1β at various severity categories and stages of AP. METHODS Plasma from 20 patients with early mild AP (MAP) (symptom onset < 72 h), 7 with severe AP (SAP) without and 4 with persistent organ failure (OF) at sampling, 8 patients with late SAP and 20 healthy controls (HC) were studied by ELISAs. RESULTS Early sST2 and IL-6 levels predicted the development of SAP and were higher in both MAP and early and late SAP than in HC. RIPK3 levels were higher than in HC in the patients who had or would later have SAP. MLKL levels were associated with the presence of OFs, particularly in the late phase, but were also higher in MAP than in HC. CONCLUSIONS sST2, RIPK3 and IL-6 levels may have prognostic value in AP. Elevated MLKL levels are associated with OF in AP. Better understanding of necroptosis in AP pathophysiology is needed to evaluate whether inhibiting and targeting necroptosis is a potential therapeutic option in AP.
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Affiliation(s)
- Hanna Belfrage
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland.
| | - Krista Kuuliala
- Department of Bacteriology and Immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Antti Kuuliala
- Department of Bacteriology and Immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland
| | - Pauli Puolakkainen
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland
| | - Leena Kylänpää
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland
| | - Johanna Louhimo
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland
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Kınacı E, Sevinc MM, Demir A, Erdogan E, Ahlatci FA, Idiz UO. Changes in cytokines and chemokines in an acute pancreatitis model. ULUS TRAVMA ACIL CER 2024; 30:229-235. [PMID: 38634842 PMCID: PMC11065975 DOI: 10.14744/tjtes.2024.18049] [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: 10/25/2023] [Revised: 03/09/2024] [Accepted: 03/29/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND The immune response secondary to inflammation that develops in acute pancreatitis plays an important role in the clinical course of the disease. This study aims to evaluate the changes in various cytokines and chemokines according to the severity of pancreatitis. METHODS Twenty-one female Wistar albino rats were divided into three equal groups. The control group received no intervention. Intraperitoneal cerulein was administered to the other groups once per hour for five hours at doses of 50 µg/kg and 80 µg/kg for the mild and severe pancreatitis groups, respectively. The development of pancreatitis and its severity level were confirmed by histological evaluation after euthanization. Blood samples were taken from all rats to measure levels of Interleukin-10 (IL-10), Interferon gamma (IFN-γ), C-X-C Motif Chemokine Ligand 1 (CXCL-1), Monocyte Chemoattractant Protein-1 (MCP-1), Tumor Necrosis Factor alpha (TNF-α), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), IL-18, IL-12p70, IL-1β, IL-17A, IL-33, IL-1α, and IL-6. Additionally, the Schoenberg inflammation scores of pancreatic tissues were evaluated. RESULTS The acute pancreatitis model was successfully induced in all cases within the study groups, according to histopathological examination. It was found that the levels of CXCL-1, MCP-1, and IL-6 were statistically significantly higher in rats with pancreatitis, with these parameters being elevated in the group with severe pancreatitis. In correlation analyses, MCP-1 and IL-6 showed a moderate correlation with the severity of pancreatitis. CONCLUSION CXCL-1, MCP-1, and IL-6 exhibit predictive characteristics for the occurrence and clinical course of pancreatitis. Our results highlight the production and working pathways of these cytokines as potential targets for therapeutic intervention.
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Affiliation(s)
- Erdem Kınacı
- Department of Liver Transplantation and HPB Surgery, Basaksehir Cam and Sakura City Hospital, İstanbul-Türkiye
| | - Mert Mahsuni Sevinc
- Department of General Surgery, Istanbul Training and Research Hospital, İstanbul-Türkiye
| | - Anil Demir
- Department of General Surgery, Istanbul Training and Research Hospital, İstanbul-Türkiye
| | - Emre Erdogan
- Ercis Martyr Ridvan Cevik State Hospital, Van-Türkiye
| | | | - Ufuk Oguz Idiz
- Department of General Surgery, Istanbul Training and Research Hospital, İstanbul-Türkiye
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Idiz UO, Aru B, Kaya C, Peker KD, Tatar C, Guler M, Tunay A, Demirel GY, Gurol AO. Could we use PD-1 and PD-L1 expression on lymphocytes and monocytes as predictive markers for prognosis of acute biliary pancreatitis? Immunol Lett 2024; 265:37-43. [PMID: 38199503 DOI: 10.1016/j.imlet.2024.106836] [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: 09/10/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 01/12/2024]
Abstract
PURPOSE This study aimed to assess the significance of immunophenotyping and serum cytokines in predicting the clinical progression of acute biliary pancreatitis (ABP). MATERIALS AND METHODS Cytokine levels, T-helper, cytotoxic T, natural killer (NK) cells, monocytes, HLA-DR, and PD-1, as well as PDL-1 immune checkpoints, were measured in ABP patients at the time of diagnosis and compared with results from healthy volunteers. The study also compared leukocyte counts, hematocrit, immunophenotyping results, cytokine statuses, and PD-1, PDL-1 expression between healthy volunteers and ABP subgroups categorized by pancreatitis severity. RESULTS The study included 65 ABP patients and 20 healthy volunteers. Significant differences were observed between groups in hematocrit, leukocyte counts, total monocytes, lymphocytes, CD3+ total T cells, CD4+ Th cells, PD-1 expression on CD4+ and CD8+T lymphocytes, HLA-DR expression on CD14+ monocytes, NK cells, PD-L1 expression on CD14+ monocytes, classical and intermediate monocytes, as well as levels of IL-6, IL-8, IL-10, IL-18, and IL-33 cytokines. Moderate correlations were found with lymphocyte counts, PD-1+CD4+ cells, PD-L1+CD14+ cells, and strong correlations with HLA-DR+CD14+ cells. Hematocrit, CD3+ total T cells, NK cells, CD4+PD-1 + T cells, and CD8+PD-1 + T cells showed independent associations with the severity of ABP. Lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, CD4+PD-1 + T cells, classical, and intermediate monocytes exhibited the highest Area Under the Curve rates in determining organ failure. CONCLUSIONS Hematocrit, lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, and intermediate monocytes emerged as parameters most closely associated with the severity and these parameters could be useful in predicting the severity of ABP.
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Affiliation(s)
- Ufuk Oguz Idiz
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey; Institute of Health Sciences, Istanbul University, Istanbul, Turkey; Department of Immunology, Istanbul University, DETAE, Istanbul, Turkey.
| | - Basak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey
| | - Cemal Kaya
- Department of General Surgery, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Kivanc Derya Peker
- Department of General Surgery, Hisar Hospital Intercontinental, Istanbul, Turkey
| | - Cihad Tatar
- Department of General Surgery, Acibadem University, Istanbul, Turkey
| | - Mert Guler
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey
| | - Abdurrahman Tunay
- Department of Anesthesia and Reanimation, Istanbul Training and Research Hospital, Istanbul, Turkey
| | | | - Ali Osman Gurol
- Department of Immunology, Istanbul University, DETAE, Istanbul, Turkey
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Mores MG, Fikry EM, El-Gendy AO, Mohamed WR, Badary OA. Probiotics mixture and taurine attenuate L-arginine-induced acute pancreatitis in rats: Impact on transient receptor potential vanilloid-1 (TRPV-1)/IL-33/NF-κB signaling and apoptosis. Tissue Cell 2023; 85:102234. [PMID: 37844391 DOI: 10.1016/j.tice.2023.102234] [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: 08/15/2023] [Revised: 10/01/2023] [Accepted: 10/05/2023] [Indexed: 10/18/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disorder of acinar cells. It may develop into severe chronic pancreatitis with a significant mortality rate. The current study aimed to assess the therapeutic effect of a Lactobacillus (LAB) mixture against rat AP. Six groups were created including control, taurine (300 mg/kg; i.p.) for 7 days, LAB mixture for 7 days, L-arginine (2.5 g/kg; i.p.) 2 doses with 1 h interval on 1st day, L-arginine+taurine, and L-arginine+LAB. Serum amylase and lipase activities were measured. Pancreatic tissue was used for histopathological examination, oxidative stress biomarkers including malondialdehyde (MDA) and reduced glutathione (GSH), and inflammatory biomarkers including myeloperoxidase (MPO) and interleukin (IL)-33 assessment. qRT-PCR was used for transient receptor potential vanilloid-1 (TRPV-1) investigation and Western blot analysis for measuring nuclear factor kappa-B (NF-κBp65) and the apoptosis biomarker; caspase-3. Taurine and LAB reduced lipase and significantly ameliorated induced oxidative stress by normalizing MDA and GSH contents. They counteracted inflammation by reducing MPO, IL-33, NF-κBp65, and TRPV-1. In addition, taurine and LAB counteracted apoptosis as proved by reduced caspase-3 expression. Taken together, these findings indicate that taurine and the use LAB mixture can mitigate AP by L-arginine via influencing TRPV-1/IL-33/NF-κB signaling together with exhibiting potent antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Marvy G Mores
- Pharmacology Department, Egyptian Drug Authority, (previously, National Organization for Drug Control and Research), Giza, Egypt
| | - Ebtehal Mohammad Fikry
- Pharmacology Department, Egyptian Drug Authority, (previously, National Organization for Drug Control and Research), Giza, Egypt
| | - Ahmed O El-Gendy
- Microbiology and Immunology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
| | - Osama A Badary
- Clinical Pharmacy Department, Faculty of Pharmacy, Misr University for Science and Technology, Cairo, Egypt; Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Wiley MB, Mehrotra K, Bauer J, Yazici C, Bialkowska AB, Jung B. Acute Pancreatitis: Current Clinical Approaches, Molecular Pathophysiology, and Potential Therapeutics. Pancreas 2023; 52:e335-e343. [PMID: 38127317 PMCID: PMC11913250 DOI: 10.1097/mpa.0000000000002259] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 06/28/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients. MATERIALS AND METHODS A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP. RESULTS Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP. CONCLUSIONS Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.
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Affiliation(s)
- Mark B Wiley
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Kunaal Mehrotra
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Jessica Bauer
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Cemal Yazici
- Department of Medicine, University of Illinois Chicago, Chicago, IL
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY
| | - Barbara Jung
- From the Department of Medicine, University of Washington, Seattle, WA
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El-Sawy SA, Amin YA, El-Naggar SA, Abdelsadik A. Artemisia annua L. (Sweet wormwood) leaf extract attenuates high-fat diet-induced testicular dysfunctions and improves spermatogenesis in obese rats. JOURNAL OF ETHNOPHARMACOLOGY 2023; 313:116528. [PMID: 37127141 DOI: 10.1016/j.jep.2023.116528] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 05/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Artemisia annua L., known as "sweet wormwood," is widely used in Egyptian folk medicine. Egyptians implement the aerial parts in the treatment of respiratory, digestive and sexual dysfunctions. However, the mechanism by which Artemisia annua improves testicular function is still being discovered. AIM OF THE STUDY This study aimed to evaluate the modulatory effects of the crude leaf extract of Artemisia annua (AAE) on a high-fat diet induced testicular dysfunction in rats and compare it with the antilipolytic drug Orlistat. MATERIAL AND METHODS Forty adult rats were randomly classified and assigned to four groups. The first group typically consumed a balanced diet and served as a negative control (GP1). A high-fat diet-induced obesity was applied to the other three groups for 12 weeks. A positive control remained on HFD for another 8 weeks, which is GP2. Other groups were administered for 8 consecutive weeks either with Orlistat (50 mg/kg body weight) or AAE (100 mg/kg body weight), which have been defined as GP3 and GP4, respectively. Testosterone (TST), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were determined in the sera of all groups. In addition, the oxidant/antioxidant biomarkers such as protein carbonyl, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) activities, lactate dehydrogenase (LDH) and creatine kinase isoenzyme-B (CK-MB) were determined. An immunohistochemical stain with the apoptotic marker caspase-3 and the proliferating cell nuclear antigen (PCNA) were also investigated. RESULTS In the testes of the obese group, the results showed hormonal imbalance, an increase in oxidative stress biomarkers and apoptosis. In the group treated with orlistat (GP3), noticeably more perturbations were noted. The obese rats that had been treated with AAE (GP4) showed a significantly reduced level of oxidative stress, hormonal balance restoration and reduced apoptosis. CONCLUSIONS The crude leaf extract of A. annua is a potential herbal therapeutic for the treatment of obesity-related testicular dysfunction and the restoration of hormonal imbalance in obese rats.
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Affiliation(s)
- Samer A El-Sawy
- Biochemistry Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Yahia A Amin
- Theriogenology Department, Faculty of Veterinary Medicine, Aswan University, Aswan, Egypt.
| | - Sabry A El-Naggar
- Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
| | - Ahmed Abdelsadik
- Zoology Department, Faculty of Science, Aswan University, Aswan, Egypt; Laboratory of Immunometabolism, Aswan University, Egypt
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Meyerholz DK, Leidinger MR, Goeken JA, Businga TR, Akers A, Vizuett S, Kaemmer CA, Kohlmeyer JL, Dodd RD, Quelle DE. Utility of CD138/syndecan-1 immunohistochemistry for localization of plasmacytes is tissue-dependent in B6 mice. BMC Res Notes 2022; 15:219. [PMID: 35752869 PMCID: PMC9233769 DOI: 10.1186/s13104-022-06100-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/07/2022] [Indexed: 11/30/2022] Open
Abstract
Objective Inflammation is present in many diseases and identification of immune cell infiltration is a common assessment. CD138 (syndecan-1) is a recommended immunohistochemical marker for human plasmacytes although it is also expressed in various epithelia and tumors. Similarly, CD138 is a marker for murine plasmacytes, but its tissue immunostaining is not well-defined. Endogenous CD138 expression is an important confounding factor when evaluating plasmacyte infiltration. We studied two plasmacyte markers (CD138 and Kappa light chains) for endogenous immunostaining in five organs and one tumor from B6 mice. Results Plasmacytes in Peyer’s patches were positive for CD138 and Kappa markers without endogenous immunostaining. Endogenous CD138 immunostaining was widespread in liver, kidney, lung and a malignant peripheral nerve sheath tumor (MPNST) versus regionalized immunostaining in skin and small intestine wall. Endogenous Kappa immunostaining was absent in all tissues except for plasmacytes. Tissues with widespread endogenous CD138 immunostaining were contrasted by absence of endogenous Kappa immunostaining. Here, plasmacytes would not be distinguished by CD138, but would be obvious by Kappa immunostaining. Our study suggests that utility of immunostaining for plasmacytes by CD138 is tissue dependent in mice. Additionally, Kappa immunostaining may be a useful alternative in mouse tissues with confounding endogenous CD138 immunostaining.
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Affiliation(s)
| | | | - J Adam Goeken
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | | | - Allison Akers
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | | | - Courtney A Kaemmer
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA
| | | | - Rebecca D Dodd
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
| | - Dawn E Quelle
- Department of Pathology, University of Iowa, Iowa City, IA, USA.,Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA
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Yang X, Chen J, Wang J, Ma S, Feng W, Wu Z, Guo Y, Zhou H, Mi W, Chen W, Yin B, Lin Y. Very-low-density lipoprotein receptor-enhanced lipid metabolism in pancreatic stellate cells promotes pancreatic fibrosis. Immunity 2022; 55:1185-1199.e8. [PMID: 35738281 DOI: 10.1016/j.immuni.2022.06.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/22/2022] [Accepted: 05/31/2022] [Indexed: 11/05/2022]
Abstract
Lipoprotein disorder is a common feature of chronic pancreatitis (CP); however, the relationship between lipoprotein disorder and pancreatic fibrotic environment is unclear. Here, we investigated the occurrence and mechanism of pancreatic stellate cell (PSC) activation by lipoprotein metabolites and the subsequent regulation of type 2 immune responses, as well as the driving force of fibrotic aggressiveness in CP. Single-cell RNA sequencing revealed the heterogeneity of PSCs and identified very-low-density lipoprotein receptor (VLDLR)+ PSCs that were characterized by a higher lipid metabolism. VLDLR promoted intracellular lipid accumulation, followed by interleukin-33 (IL-33) expression and release in PSCs. PSC-derived IL-33 strongly induced pancreatic group 2 innate lymphoid cells (ILC2s) to trigger a type 2 immune response accompanied by the activation of PSCs, eventually leading to fibrosis during pancreatitis. Our findings indicate that VLDLR-enhanced lipoprotein metabolism in PSCs promotes pancreatic fibrosis and highlight a dominant role of IL-33 in this pro-fibrotic cascade.
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Affiliation(s)
- Xuguang Yang
- Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China.
| | - Jie Chen
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Department of Pediatric Surgery, Jiaxing Maternity and Child Health Care Hospital Affiliated to Jiaxing University, Jiaxing 314000, China
| | - Jun Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Shuai Ma
- Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Wenxue Feng
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Zhihao Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Yangyang Guo
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Hong Zhou
- Department of Immunology, Anhui Medical University, Hefei, An Hui 230031, China
| | - Wenli Mi
- Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Wei Chen
- Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Bo Yin
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200032, China.
| | - Yuli Lin
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China.
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Inhibition of Spinal Interleukin-33 Attenuates Peripheral Inflammation and Hyperalgesia in Experimental Arthritis. Mol Neurobiol 2022; 59:2246-2257. [PMID: 35066763 DOI: 10.1007/s12035-022-02754-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/17/2022] [Indexed: 10/19/2022]
Abstract
Accumulating evidence indicates that the continuous and intense nociceptive from inflamed tissue may increase the excitability of spinal dorsal horn neurons, which can signal back and modulate peripheral inflammation. Previous studies have demonstrated that spinal interleukin (IL)-33 contributes to the hyperexcitability of spinal dorsal horn neurons. This study was undertaken to investigate whether spinal IL-33 can also influence a peripheral inflammatory response in a rat model of arthritis. Lentivirus-delivered short hairpin RNA targeting IL-33 (LV-shIL-33) was constructed for gene silencing. Rats with adjuvant-induced arthritis (AIA) were injected intrathecally with LV-shIL-33 3 days before the complete Freund's adjuvant (CFA) injection. During an observation period of 21 days, pain-related behavior and inflammation were assessed. In addition, the expression of spinal proinflammatory cytokines and the activation of spinal extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB) pathways were evaluated on 9 days after CFA treatment. The existence of tissue injury or inflammation in rats with AIA resulted in the upregulation of spinal IL-33, which is predominantly expressed in neurons, astrocytes, and oligodendrocytes. Intrathecal administration of LV-shIL-33 significantly alleviated hyperalgesia, paw swelling, and joint destruction, and attenuated the expression of proinflammatory cytokines [IL-6, IL-1β, and tumor necrosis factor-α (TNF-α)], as well as the activation of ERK and NF-κB/p65 in the spinal cord. Our data suggest that spinal IL-33 contributes to the development of both peripheral inflammation and hyperalgesia. Thus, interference with IL-33 at the spinal level might represent a novel therapeutic target for painful inflammatory disorders.
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11
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Zhang Y, Cheng B, Wu ZW, Cui ZC, Song YD, Chen SY, Liu YN, Zhu CJ. Serum soluble suppression of tumorigenicity 2 as a novel inflammatory marker predicts the severity of acute pancreatitis. World J Gastroenterol 2021; 27:6489-6500. [PMID: 34720537 PMCID: PMC8517782 DOI: 10.3748/wjg.v27.i38.6489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 06/10/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory disease in which the regulatory pathway is complex and not well understood. Soluble suppression of tumorigenicity 2 (sST2) protein receptor functions as a decoy receptor for interleukin (IL)-33 to prevent IL-33/suppression of tumorigenicity 2L (ST2L)-pathway-mediated T helper (Th)2 immune responses.
AIM To investigate the role of sST2 in AP.
METHODS We assessed the association between sST2 and severity of AP in 123 patients enrolled in this study. The serum levels of sST2, C-reactive protein (CRP) and Th1- and Th2-related cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-2, IL-4, IL-5 and IL-13, were measured by highly sensitive ELISA, and the severity of AP in patients was evaluated by the 2012 Atlanta Classification Criteria.
RESULTS Serum sST2 levels were significantly increased in AP patients, and further, these levels were significantly elevated in severe AP (SAP) patients compared to moderately severe AP (MSAP) and mild AP (MAP) patients. Logistic regression showed sST2 was a predictor of SAP [odds ratio (OR): 1.003 (1.001–1.006), P = 0.000]. sST2 cutoff point was 1190 pg/mL, and sST2 above this cutoff was associated with SAP. sST2 was also a predictor of any organ failure and mortality during AP [OR: 1.006 (1.003–1.009), P = 0.000, OR: 1.002 (1.001–1.004), P = 0.012, respectively]. Additionally, the Th1-related cytokines IFN-γ and TNF-α in the SAP group were higher and the Th2-related cytokine IL-4 in the SAP group was significantly lower than those in MSAP and MAP groups.
CONCLUSION sST2 may be used as a novel inflammatory marker in predicting AP severity and may regulate the function and differentiation of IL-33/ST2-mediated Th1 and Th2 Lymphocytes in AP homeostasis.
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Affiliation(s)
- Yan Zhang
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bo Cheng
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhong-Wei Wu
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zong-Chao Cui
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yao-Dong Song
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - San-Yang Chen
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan-Na Liu
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Chang-Ju Zhu
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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12
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Zhou J, Zhuang T, Ma P, Shan L, Sun XD, Gong S, Tao J, Yu XM, Jiang X. MicroRNA-547-5p-mediated interleukin-33/suppressor of tumorigenicity 2 signaling underlies the genesis and maintenance of neuropathic pain and is targeted by the therapy with bone marrow stromal cells. Mol Pain 2021; 16:1744806920931737. [PMID: 32513089 PMCID: PMC7309409 DOI: 10.1177/1744806920931737] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) signaling is known to promote inflammation and the genesis and maintenance of neuropathic pain. However, it remained mostly unknown how IL-33/ST2 signaling can be enhanced by neuropathic stimulations. Here, we report that the chronic constriction nerve injury (CCI)-induced increases in the expression of IL-33 and ST2 and a decrease in microRNA (miRNA)-547-5p not only in the dorsal root ganglia (DRG) but also in spinal dorsal horn (SDH) ipsilateral to the CCI. We found that increasing endogenous miRNA-547-5p by the intrathecal (i.t.) infusion of agomir-miR-547-5p did not produce any effect in naive rats but blocked the CCI-induced increases in the IL-33 and ST2, and pain sensitivity. The reducing endogenous miRNA-547-5p by the i.t. delivering antagomir-miR-547-5p into naive rats caused significant changes in IL-33 and ST2 expressions in both the DRG and SDH, and pain sensitivity, which were similar to those induced by the CCI. Since increasing IL-33 by the i.t. infusion of recombinant IL-33 produced no change in the expression of miR-547-5p, and the CCI still reduced miR-547-5p expression in rats with the IL-33 knockdown, we conclude that the reduction of miR-547-5p can be an upstream event leading to the enhancement of IL-33/ST2 signaling induced by the CCI. The intravenous application of bone marrow stromal cells (BMSCs) reduced the depression of miR-547-5p in both the DRG and SDH, and pain hypersensitivity produced by the CCI or antagomir-miR547-5p application. However, the BMSC effect was significantly occluded by the pretreatment with miR-547-5p agomir or the IL-33 knockdown, demonstrating a novel mechanism underlying the BMSC therapy.
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Affiliation(s)
- Ju Zhou
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Ting Zhuang
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Peng Ma
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Lidong Shan
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Xiao-Dong Sun
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Shan Gong
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Jin Tao
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Xian-Min Yu
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
| | - Xinghong Jiang
- Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou, China
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13
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Interleukin-33 modulates lipopolysaccharide-mediated inflammatory response in rat primary astrocytes. Neuroreport 2021; 32:694-701. [PMID: 33913926 DOI: 10.1097/wnr.0000000000001644] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Astrocytes have a crucial role in the modulation of the neuroinflammatory response. However, the underlying mechanisms have yet to be fully defined. Interleukin-33 (IL-33) is constitutively expressed in astrocytes, which has been found to orchestrate inflammatory responses in a large variety of immune-mediated and inflammatory diseases of the nervous system. Thus, the purpose of this study was to elucidate the potential effect of IL-33 in the regulation of inflammatory response in primary cultured astrocytes. We investigated the role of IL-33 in the regulation of inflammatory responses in the lipopolysaccharide-stimulated astrocytes. This study utilized lentiviral short hairpin RNA vectors to target IL-33 (LV-shIL-33) for gene silencing. After lipopolysaccharide stimulation, the expression levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as the activation of nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) signaling pathways, were evaluated to elucidate the mechanisms related to the contributions of IL-33 to the inflammatory response in astrocytes. We found that the expression IL-33 has increased in rat primary cultured astrocytes after lipopolysaccharide stimulation. Administration of LV-shIL-33 knocked down the expression of IL-33 and markedly reduced the overexpression of spinal IL-1β, IL-6, and TNF-α, and attenuated the activation of ERK and NF-κB/p65. This study shows that IL-33 participates in regulating inflammatory responses in primary cultured astrocytes, which might provide additional targets for controlling inflammatory responses following neurological diseases. See Video abstract, http://links.lww.com/WNR/A627.
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14
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Peng C, Li Z, Yu X. The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis. Int J Med Sci 2021; 18:534-545. [PMID: 33390823 PMCID: PMC7757151 DOI: 10.7150/ijms.51618] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is a leading cause of gastrointestinal-related hospital admissions with significant morbidity and mortality. Although the underlying pathophysiology of AP is rather complex, which greatly limits the treatment options, more and more studies have revealed that infiltrating immune cells play a critical role in the pathogenesis of AP and determine disease severity. Thus, immunomodulatory therapy targeting immune cells and related inflammatory mediators is expected to be a novel treatment modality for AP which may improve the prognosis of patients. Cells of the innate immune system, including macrophages, neutrophils, dendritic cells, and mast cells, represent the majority of infiltrating cells during AP. In this review, an overview of different populations of innate immune cells and their role during AP will be discussed, with a special focus on neutrophils and macrophages.
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Affiliation(s)
- Cheng Peng
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Zhiqiang Li
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xiao Yu
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
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15
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Abdel Hafez SMN, Allam FAFA, Elbassuoni E. Sex differences impact the pancreatic response to chronic immobilization stress in rats. Cell Stress Chaperones 2021; 26:199-215. [PMID: 32986228 PMCID: PMC7736456 DOI: 10.1007/s12192-020-01169-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/21/2020] [Accepted: 09/24/2020] [Indexed: 12/27/2022] Open
Abstract
Chronic stress has been related to multiple diseases. Inflammation is proposed strongly to link stress to stress-related diseases in different organs, such as small intestine, colon, and brain. However, stress cellular effect on the pancreatic tissue, especially the exocrine one, had received relatively little attention. This work aimed to evaluate the cellular effect of chronic immobilization stress on the pancreatic tissue function and structure along with evaluating the sex role in this type of pancreatic injury. Thirty rats were equally divided into 5 groups: control male, control female, stressed male, stressed female, and stressed female with bilateral ovariectomy. Stressed rats were exposed to immobilization for 1 h/day, 6 days/week, for 3 weeks. Rats were then decapitated for further biochemical, histological, histo-morphometric, and immunohistochemical study. The results showed that, in male and female rats, chronic immobilization stress produced hypoinsulinemia and hyperglycemia, with increasing exocrine pancreatic injury markers by increasing oxidative and inflammatory status of the pancreatic tissue, and exhibited a degenerative effect on the pancreatic tissue. However, the stress-induced pancreatic effects were more obvious in male rats and female rats with bilateral ovariectomy than that in female rats. It could be concluded that male animals were more susceptible to stress-induced pancreatic damage than females. The ovarian hormones are responsible, at least partly, for pancreatic tissue protection since the stress-induced pancreatic injury in females was exacerbated by ovariectomy. In this study, inflammatory and oxidative stress differences in both sexes could provide a plausible explanation for sex differences.
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Affiliation(s)
| | | | - Eman Elbassuoni
- Physiology Department, Faculty of Medicine, Minia University, Minia, Egypt
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16
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Ge P, Luo Y, Okoye CS, Chen H, Liu J, Zhang G, Xu C, Chen H. Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: A troublesome trio for acute pancreatitis. Biomed Pharmacother 2020; 132:110770. [PMID: 33011613 DOI: 10.1016/j.biopha.2020.110770] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/11/2020] [Accepted: 09/17/2020] [Indexed: 02/08/2023] Open
Abstract
Severe acute pancreatitis (SAP), a serious inflammatory disease of the pancreas, can easily lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS). Acute lung injury (ALI) is one of the most serious complications of SAP. However, the specific pathogenesis of SAP-associated ALI is not fully understood. Crosstalk and multi-mechanisms involving pancreatic necrosis, bacteremia, intestinal barrier failure, activation of inflammatory cascades and diffuse alveolar damage is the main reason for the unclear pathological mechanism of SAP-associated ALI. According to previous research on SAP-associated ALI in our laboratory and theories put forward by other scholars, we propose that the complex pattern of SAP-associated ALI is based on the "pancreas-intestine-inflammation/endotoxin-lung (P-I-I/E-L) pathway". In this review, we mainly concentrated on the specific details of the "P-I-I/E-L pathway" and the potential treatments or preventive measures for SAP-associated ALI.
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Affiliation(s)
- Peng Ge
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China
| | - Yalan Luo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China
| | - Chukwuemeka Samuel Okoye
- Orthopedic Research Center, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, PR China
| | - Haiyang Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China
| | - Jiayue Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China
| | - Guixin Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China
| | - Caiming Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China.
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China; Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, PR China.
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17
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Alcohol and Smoking Mediated Modulations in Adaptive Immunity in Pancreatitis. Cells 2020; 9:cells9081880. [PMID: 32796685 PMCID: PMC7463831 DOI: 10.3390/cells9081880] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatitis is a condition of pancreatic inflammation driven by injury to the pancreatic parenchyma. The extent of acinar insult, intensity, and type of immune response determines the severity of the disease. Smoking, alcohol and autoimmune pancreatitis are some of the predominant risk factors that increase the risk of pancreatitis by differentially influencing the adaptive immune system. The overall decrease in peripheral lymphocyte (T-, B- and (natural killer T-) NKT-cell) count and increased infiltration into the damaged pancreatic tissue highlight the contribution of adaptive immunity in the disease pathology. Smoking and alcohol modulate the responsiveness and apoptosis of T- and B-cells during pancreatic insult. Acute pancreatitis worsens with smoking and alcohol, leading to the development of systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome, suggesting the critical role of adaptive immunity in fatal outcomes such as multiple organ dysfunction. The presence of CD4+ and CD8+ T-lymphocytes and perforin-expressing cells in the fibrotic tissue in chronic pancreatitis modulate the severity of the disease. Due to their important role in altering the severity of the disease, attempts to target adaptive immune mediators will be critical for the development of novel therapeutic interventions.
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18
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Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis. Int J Mol Sci 2020; 21:5386. [PMID: 32751171 PMCID: PMC7432368 DOI: 10.3390/ijms21155386] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
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19
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Ruan Q, Lu H, Zhu H, Guo Y, Bai Y. A network-regulative pattern in the pathogenesis of kidney injury following severe acute pancreatitis. Biomed Pharmacother 2020; 125:109978. [DOI: 10.1016/j.biopha.2020.109978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/17/2020] [Accepted: 01/27/2020] [Indexed: 01/04/2023] Open
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20
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Yang Q, Gao P, Mu M, Tao X, He J, Wu F, Guo S, Qian Z, Song C. [Phagocytosis of alveolar macrophages is suppressed in a mouse model of lipopolysaccharide-induced acute lung injury]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:376-381. [PMID: 32376590 DOI: 10.12122/j.issn.1673-4254.2020.03.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the changes in phagocytic function of alveolar macrophages (AMs) in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore the possible mechanism. METHODS Kunming mice were randomly divided into normal control group and ALI (induced by LPS instillation in the airway) model group. AMs were obtained from bronchoalveolar lavage fluid in both groups, and phagocytosis of the AMs was observed using flow cytometry and fluorescence microscopy. Western blotting and ELISA were used to detect the expression and secretion of IL-33 in the lung tissue of the mice. We also detected the secretion of IL-33 by an alveolar epithelial cell line MLE-12 in response to stimulation with different concentrations of LPS. The AMs from the normal control mice were treated with different concentrations of LPS and IL-33, and the changes in the phagocytic activity of the cells were observed. RESULTS Compared with those in normal control group, the percentage of AMs phagocytosing fluorescent microspheres was significantly decreased, and the expression of IL-33 in lung tissue and IL-33 level in the bronchoalveolar lavage fluid were significantly increased in ALI mice (P < 0.01). LPS (100-1000 ng/mL) obviously promoted the secretion of IL-33 in cultured MLE-12 cells (P < 0.01). Both LPS (10-500 ng/mL) and IL-33 (100 ng/mL) significantly inhibited the phagocytic activity of the AMs from normal control mice (P < 0.01). CONCLUSIONS The phagocytic activity of AMs is weakened in ALI mice possibly due to direct LPS stimulation and the inhibitory effect of the alarmin IL-33 produced by LPS-stimulated alveolar epithelial cells.
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Affiliation(s)
- Qian Yang
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Peiyu Gao
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Mimi Mu
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Xiangnan Tao
- Department of Clinical Laboratory, Second Affiliated Hospital of Bengbu Medical College, Bengbu 233040, China
| | - Jing He
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Fengjiao Wu
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Shujun Guo
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Zhongqing Qian
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Chuanwang Song
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
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21
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Abdolmohammadi K, Mahmoudi T, Nojehdehi S, Tayebi L, Hashemi SM, Noorbakhsh F, Abdollahi A, Soleimani M, Nikbin B, Nicknam MH. Effect of Hypoxia Preconditioned Adipose-Derived Mesenchymal Stem Cell Conditioned Medium on Cerulein-Induced Acute Pancreatitis in Mice. Adv Pharm Bull 2020; 10:297-306. [PMID: 32373500 PMCID: PMC7191232 DOI: 10.34172/apb.2020.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose: Acute pancreatitis (AP) is an inflammatory disorder distinguished by tissue injury and inflammation of the pancreas. Using paracrine potential of mesenchymal stem cells (MSCs) provides a useful clinical approach in treating inflammatory diseases. We investigated the therapeutic effects of adipose-derived MSC conditioned medium (CM) and hypoxia preconditioned adipose-derived MSC conditioned medium (HCM) in cerulein-induced AP in mice. Methods: AP was induced in C57BL/6 mice by intraperitoneal injection of cerulein (75 μg/ kg/h × 7 times). One hour following the last injection of cerulein, mice were treated with intraperitoneal injection of CM and HCM (500 µL/mice/30 min × 3 times). Twelve hours following the treatment, serum levels of amylase and lipase were measured. In addition, pancreas pathological changes, immunohistochemical examinations for evaluation of IL-6 expression and pancreatic myeloperoxidase (MPO) enzyme activity were analyzed. Results: The in vitro results of the morphological, differentiation and immunophenotyping analyses confirmed that hypoxia preconditioned MSCs (HP-MSCs) conserve MSCs characteristics after preconditioning. However, HP-MSCs significantly expressed high mRNA level of hypoxia inducible factor 1-α and higher level of total protein. The in vivo findings of the current study showed that CM and HCM significantly reduced the amylase & lipase activity, the severity of pancreas tissue injury and the expression of IL-6 and MPO enzyme activity compared with the AP group. However, no significant difference between CM and HCM groups was demonstrated. Conclusion: Use of CM and HCM can attenuate cerulein-induced AP and decrease inflammation in the pancreas tissue in AP mice.
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Affiliation(s)
- Kamal Abdolmohammadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Mahmoudi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Seyed Mahmoud Hashemi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Abdollahi
- Department of Pathology, School of Medicine, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.,Breast Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Behrouz Nikbin
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Renoprotective effect of calycosin in high fat diet-fed/STZ injected rats: Effect on IL-33/ST2 signaling, oxidative stress and fibrosis suppression. Chem Biol Interact 2020; 315:108897. [DOI: 10.1016/j.cbi.2019.108897] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 10/30/2019] [Accepted: 11/08/2019] [Indexed: 12/29/2022]
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Babina M, Wang Z, Franke K, Guhl S, Artuc M, Zuberbier T. Yin-Yang of IL-33 in Human Skin Mast Cells: Reduced Degranulation, but Augmented Histamine Synthesis through p38 Activation. J Invest Dermatol 2019; 139:1516-1525.e3. [PMID: 30684550 DOI: 10.1016/j.jid.2019.01.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/13/2018] [Accepted: 01/08/2019] [Indexed: 12/13/2022]
Abstract
Mast cells (MCs) are the principal effector cells of IgE-mediated allergy. IL-33 is released by resident skin cells as alarmin upon tissue damage or allergen contact. Owing to their pronounced receptor expression, MCs are important targets of IL-33 action, but consequences for skin MCs are ill-defined, especially upon chronic exposure to IL-33. Mimicking the inflammatory milieu of skin disorders, we found that persistent exposure to IL-33 (over a 5-week period) strengthened skin MC numbers through accelerated cell-cycle progression and restriction of apoptosis. Conversely, IL-33 attenuated degranulation and FcεRI expression, potentially as a feedback to chronic "alarmin" exposure. Interestingly, the negative impact on histamine release was counterbalanced by amplified histamine production. Considering the clinical significance of histamine and scarce information on its regulation, we explored the molecular underpinnings. IL-33 induced swift phosphorylation of p38 and JNK (but not of ERK1/2 or AKT), and stimulated histidine decarboxylase expression. Combining pharmacological inhibition and kinase elimination by Accell-facilitated RNA interference in skin MCs revealed a p38-dependent, but JNK-independent mechanism. Collectively, IL-33 exerts multifaceted effects on cutaneous MCs at a post-maturation stage. The IL-33-skin MC axis may contribute to and balance inflammation in chronic skin disorders.
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Affiliation(s)
- Magda Babina
- Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
| | - Zhao Wang
- Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Kristin Franke
- Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sven Guhl
- Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Metin Artuc
- Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Torsten Zuberbier
- Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Frossi B, Mion F, Sibilano R, Danelli L, Pucillo CEM. Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity? Immunol Rev 2019; 282:35-46. [PMID: 29431204 DOI: 10.1111/imr.12636] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mast cells (MCs) are derived from committed precursors that leave the hematopoietic tissue, migrate in the blood, and colonize peripheral tissues where they terminally differentiate under microenvironment stimuli. They are distributed in almost all vascularized tissues where they act both as immune effectors and housekeeping cells, contributing to tissue homeostasis. Historically, MCs were classified into 2 subtypes, according to tryptic enzymes expression. However, MCs display a striking heterogeneity that reflects a complex interplay between different microenvironmental signals delivered by various tissues, and a differentiation program that decides their identity. Moreover, tissue-specific MCs show a trained memory, which contributes to shape their function in a specific microenvironment. In this review, we summarize the current state of our understanding of MC heterogeneity that reflects their different tissue experiences. We describe the discovery of unique cell molecules that can be used to distinguish specific MC subsets in vivo, and discuss how the improved ability to recognize these subsets provided new insights into the biology of MCs. These recent advances will be helpful for the understanding of the specific role of individual MC subsets in the control of tissue homeostasis, and in the regulation of pathological conditions such as infection, autoimmunity, and cancer.
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Affiliation(s)
- Barbara Frossi
- Department of Medicine, University of Udine, Udine, Italy
| | - Francesca Mion
- Department of Medicine, University of Udine, Udine, Italy
| | - Riccardo Sibilano
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Luca Danelli
- Retroviral Immunology, The Francis Crick Institute, London, UK
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Korhonen P, Pollari E, Kanninen KM, Savchenko E, Lehtonen Š, Wojciechowski S, Pomeshchik Y, Van Den Bosch L, Goldsteins G, Koistinaho J, Malm T. Long-term interleukin-33 treatment delays disease onset and alleviates astrocytic activation in a transgenic mouse model of amyotrophic lateral sclerosis. IBRO Rep 2019; 6:74-86. [PMID: 30705990 PMCID: PMC6348738 DOI: 10.1016/j.ibror.2019.01.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 01/08/2019] [Indexed: 12/12/2022] Open
Abstract
Th2-type cytokine IL-33 delayed the disease onset of female SOD1-G93 A transgenic ALS mice. IL-33 decreased the proportion of T cells in the spleens and lymph nodes of female mice. IL-33 decreased astrocytic activation in the spinal cord of female mice. Male mice were unresponsive to the treatment. Inflammation is a prominent feature of the neuropathology of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that inflammatory cascades contributing to the disease progression are not restricted to the central nervous system (CNS) but also occur peripherally. Indeed, alterations in T cell responses and their secreted cytokines have been detected in ALS patients and in animal models of ALS. One key cytokine responsible for the shift in T cell responses is interleukin-33 (IL-33), which stimulates innate type 2 immune cells to produce a large amount of Th2 cytokines that are possibly beneficial in the recovery processes of CNS injuries. Since the levels of IL-33 have been shown to be decreased in patients affected with ALS, we sought to determine whether a long-term recombinant IL-33 treatment of a transgenic mouse model of ALS expressing G93A-superoxide dismutase 1 (SOD1-G93A) alters the disease progression and ameliorates the ALS-like disease pathology. SOD1-G93A mice were treated with intraperitoneal injections of IL-33 and effects on disease onset and inflammatory status were determined. Spinal cord (SC) neurons, astrocytes and T-cells were exposed to IL-33 to evaluate the cell specific responses to IL-33. Treatment of SOD1-G93A mice with IL-33 delayed the disease onset in female mice, decreased the proportion of CD4+ and CD8 + T cell populations in the spleen and lymph nodes, and alleviated astrocytic activation in the ventral horn of the lumbar SC. Male SOD1-G93A mice were unresponsive to the treatment. In vitro studies showed that IL-33 is most likely not acting directly on neurons and astrocytes, but rather conveying its effects through peripheral T-cells. Our results suggest that strategies directed to the peripheral immune system may have therapeutic potential in ALS. The effect of gender dimorphisms to the treatment efficacy needs to be taken into consideration when designing new therapeutic strategies for CNS diseases.
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Key Words
- ALS
- ALS, amyotrophic lateral sclerosis
- ANOVA, analysis of variance
- Arg-1, arginine-1
- Astrocyte
- CM, conditioned medium
- CNS, central nervous system
- Cytokine
- DMEM, Dulbecco’s minimum essential medium
- EAE, experimental autoimmune encephalomyelitis
- GFAP, glial fibrillary acidic protein
- HO-1, hemeoxygenase-1
- IFN-γ, interferon gamma
- IL-10, interleukin-10
- IL-1RAcP, interleukin-1 receptor accessory protein
- IL-33, interleukin-33
- IL-33R, interleukin-33 receptor
- IL-6, interleukin-6
- Iba-1, ionized calcium binding adaptor molecule-1
- Inflammation
- Interleukin-33
- MCP-1, monocyte chemoattractant protein-1
- Microglia
- NFE2L2, the gene encoding Nrf2
- Nrf2, nuclear factor (erythroid-derived 2)-like 2
- PBS, phosphate buffered saline
- RT, room temperature
- SC, spinal cord
- SD, standard deviation
- SOD1, superoxide dismutase 1
- Spinal cord
- T cell
- TG, transgenic
- TNF, tumor necrosis factor
- WT, wildtype
- fALS, familial ALS
- sALS, sporadic ALS
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Affiliation(s)
- Paula Korhonen
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Eveliina Pollari
- KU Leuven, University of Leuven, Department of Neurosciences, Experimental Neurology, VIB Center for Brain & Disease Research, Box 912, B-3000 Leuven, Belgium
| | - Katja M Kanninen
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Ekaterina Savchenko
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Šárka Lehtonen
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Sara Wojciechowski
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Yuriy Pomeshchik
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Ludo Van Den Bosch
- KU Leuven, University of Leuven, Department of Neurosciences, Experimental Neurology, VIB Center for Brain & Disease Research, Box 912, B-3000 Leuven, Belgium
| | - Gundars Goldsteins
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Jari Koistinaho
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Tarja Malm
- A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
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Watanabe T, Minaga K, Kamata K, Kudo M, Strober W. Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease. Trends Immunol 2018; 39:874-889. [PMID: 30401468 DOI: 10.1016/j.it.2018.09.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/12/2018] [Accepted: 09/13/2018] [Indexed: 12/15/2022]
Abstract
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a recently defined disease form known as IgG4-related disease (AIP/IgG4-RD). AIP/IgG4-RD is characterized by elevated systemic IgG4 antibody concentrations and lesional tissues infiltrated by IgG4-expressing plasmacytes. In addition, recent studies have revealed that, in common with other autoimmune diseases, such as systemic lupus erythematosus (SLE) and psoriasis, AIP/IgG4-RD is associated with increased type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs). However, unlike SLE, AIP/IgG4-RD is characterized by elevated IFN-I-dependent IL-33 production, the latter emerging as an important contributor to inflammation and fibrotic responses characterizing this disease. On this basis, we propose that blockade of the IFN-I/IL-33 axis might constitute a successful approach to treating this unique type of autoimmunity.
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Affiliation(s)
- Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan; Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Kotsiou OS, Gourgoulianis KI, Zarogiannis SG. IL-33/ST2 Axis in Organ Fibrosis. Front Immunol 2018; 9:2432. [PMID: 30405626 PMCID: PMC6207585 DOI: 10.3389/fimmu.2018.02432] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022] Open
Abstract
Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.
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Affiliation(s)
- Ourania S. Kotsiou
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| | - Konstantinos I. Gourgoulianis
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| | - Sotirios G. Zarogiannis
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
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28
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Khosravi AR, Alheidary S, Nikaein D, Asghari N. Aspergillus fumigatus conidia stimulate lung epithelial cells (TC-1 JHU-1) to produce IL-12, IFNγ, IL-13 and IL-17 cytokines: Modulatory effect of propolis extract. J Mycol Med 2018; 28:594-598. [PMID: 30360945 DOI: 10.1016/j.mycmed.2018.09.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 08/01/2018] [Accepted: 09/25/2018] [Indexed: 12/18/2022]
Abstract
Aspergillus fumigatus conidia are the most prevalent indoors fungal allergens. The interaction between Aspergillus antigens and lung epithelial cells (LECs) result in innate immune functions. The association between Aspergillus conidia and allergic reactions, like allergic bronchopulmonary aspergillosis (ABPA) and asthma have been repeatedly reported. Since conventional therapies for allergy and asthma are limited, finding new promising treatments are inevitable. This study was designed to evaluate the effect of A. fumigatus conidia on IL-12, IFNγ, IL-13 and IL-17 release from mouse LECs and to investigate the effect of propolis on cytokines modulation. Cells were divided to two groups, one was exposed to 3×104 conidia of Aspergillus fumigatus and another group was treated by propolis (25μg/mL) as well as exposed to A. fumigatus conidia. Cytokines IL-13, IL-12, IFNγ and IL-17 were measured at times 0, 6 and 12hours after exposure using ELISA assay. The results indicated that A. fumigatus could increase the release of the cytokines with IL-13 and IL-17 being the most affected ones whilst treatment with propolis decreased the effects of A. fumigatus on IL-13 and IL-17 production. The results showed that propolis has down regulatory effects on Th2 cytokine, IL-13, and IL-17 production, whereas it caused a significant induction of IL-12, as an important Th1 cytokines by LECs. With respect to the obtained results, propolis extract might be contributed to decrease Th2 responses in allergic asthma phenomenon. However more investigations must be done in future to fully understand its efficacy.
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Affiliation(s)
- A R Khosravi
- Mycology research center, faculty of veterinary medicine, university of Tehran, Tehran, Iran.
| | - S Alheidary
- Mycology research center, faculty of veterinary medicine, university of Tehran, Tehran, Iran
| | - D Nikaein
- Mycology research center, faculty of veterinary medicine, university of Tehran, Tehran, Iran
| | - N Asghari
- Mycology research center, faculty of veterinary medicine, university of Tehran, Tehran, Iran
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29
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Li M, Zhang X, Wang B, Xu X, Wu X, Guo M, Wang F. Effect of JAK2/STAT3 signaling pathway on liver injury associated with severe acute pancreatitis in rats. Exp Ther Med 2018; 16:2013-2021. [PMID: 30186433 DOI: 10.3892/etm.2018.6433] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 06/22/2018] [Indexed: 12/19/2022] Open
Abstract
Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling constitutes one of the major pathways for cytokine signal transduction. However, the role of the JAK2/STAT3 pathway in liver injury during severe acute pancreatitis (SAP) remains unclear. The aim of this study was to investigate the role of the JAK2/STAT3 signaling pathway in liver injury after SAP. In the present study 64 male Sprague-Dawley rats were randomly divided into four groups: Control, AG490 (inhibition of JAK2), SAP and SAP with AG490. SAP was induced by retrograde infusion of 4% sodium taurocholate into the biliopancreatic duct. The activities of amylase (AMY) and liver enzymes were measured in serum. Livers and pancreas were isolated for measurements of histological damage. Blood and liver samples were taken for the measurement of TNF-α, IL-6 and IL-18 concentrations. The expression levels of JAK2 and STAT3 in liver tissue were detected by immunohistochemical staining and western blotting. The results demonstrated that amylase and liver enzymes were higher in the SAP groups compared with the control, AG490 and AG490-treated groups. The serum levels of TNF-α, IL-6 and IL-18 were effectively increased in the SAP groups, whereas they were reduced by AG490. Interestingly, JAK2 and STAT3 protein expression levels were significantly increased following induction of SAP and were significantly decreased in the AG490-pretreated groups. Administration of AG490 decreased the activity of pro-inflammatory cytokines and significantly attenuated SAP associated-liver injury in the rats. These results suggested that the mechanism may relate to the inhibition of TNF-α, IL-6 and IL-18, and inhibiting excessive JAK2 and STAT3 activation, and may play a crucial role in the liver injury associated with SAP.
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Affiliation(s)
- Minli Li
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaohua Zhang
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Bin Wang
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaobing Xu
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaowei Wu
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Meixia Guo
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Fangyu Wang
- Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
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30
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Kempuraj D, Thangavel R, Selvakumar GP, Ahmed ME, Zaheer S, Raikwar SP, Zahoor H, Saeed D, Dubova I, Giler G, Herr S, Iyer SS, Zaheer A. Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-κB. Mol Neurobiol 2018; 56:1681-1693. [PMID: 29916143 DOI: 10.1007/s12035-018-1177-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/04/2018] [Indexed: 12/13/2022]
Abstract
Inflammatory mediators released from activated microglia, astrocytes, neurons, and mast cells mediate neuroinflammation. Parkinson's disease (PD) is characterized by inflammation-dependent dopaminergic neurodegeneration in substantia nigra. 1-Methyl-4-phenylpyridinium (MPP+), a metabolite of parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), induces inflammatory mediators' release from brain cells and mast cells. Brain cells' interaction with mast cells is implicated in neuroinflammation. However, the exact mechanisms involved are not yet clearly understood. Mouse fetal brain-derived cultured primary astrocytes and glia-neurons were incubated with mouse mast cell protease-6 (MMCP-6) and MMCP-7, and mouse bone marrow-derived mast cells (BMMCs) were incubated with MPP+ and brain protein glia maturation factor (GMF). Interleukin-33 (IL-33) released from these cells was quantitated by enzyme-linked immunosorbent assay. Both MMCP-6 and MMCP-7 induced IL-33 release from astrocytes and glia-neurons. MPP+ and GMF were used as a positive control-induced IL-33 and reactive oxygen species expression in mast cells. Mast cell proteases and MPP+ activate p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), mitogen-activated protein kinases (MAPKs), and transcription factor nuclear factor-kappa B (NF-κB) in astrocytes, glia-neurons, or mast cells. Addition of BMMCs from wt mice and transduction with adeno-GMF show higher chemokine (C-C motif) ligand 2 (CCL2) release. MPP+ activated glial cells and reduced microtubule-associated protein 2 (MAP-2) expression indicating neurodegeneration. IL-33 expression increased in the midbrain and striatum of PD brains as compared with age- and sex-matched control subjects. Glial cells and neurons interact with mast cells and accelerate neuroinflammation and these interactions can be explored as a new therapeutic target to treat PD.
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Affiliation(s)
- Duraisamy Kempuraj
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA.
| | - Ramasamy Thangavel
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Gvindhasamy Pushpavathi Selvakumar
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Mohammad Ejaz Ahmed
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Smita Zaheer
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Sudhanshu P Raikwar
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Haris Zahoor
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Daniyal Saeed
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Iuliia Dubova
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Gema Giler
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Shelby Herr
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Shankar S Iyer
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA
| | - Asgar Zaheer
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.
- Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Medical Science Building,1 Hospital Drive, Columbia, MO, 65211, USA.
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Protective Effect of Scopoletin Against Cerulein-Induced Acute Pancreatitis and Associated Lung Injury in Mice. Pancreas 2018; 47:577-585. [PMID: 29595543 DOI: 10.1097/mpa.0000000000001034] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE The present study aimed to evaluate the protective effects of scopoletin (SC) on cerulein-induced acute pancreatitis (AP) and associated lung injury in mice. METHODS Acute pancreatitis was induced in male Swiss mice by 6 consecutive hourly intraperitoneal injections of cerulein (50 μg/kg). Scopoletin was administered 1 hour (intraperitoneal, 10 mg/kg) after the first cerulein injection. RESULTS Administration of SC attenuated the severity of AP and associated lung injury as shown by histology, reduced myeloperoxidase, and serum amylase activity. Further, the anti-inflammatory effect of SC was associated with a reduction of pancreatic and pulmonary proinflammatory cytokines (interleukin 1β and tumor necrosis factor α) and hydrogen sulfide. Moreover, SC inhibited cerulein-induced nuclear factor κB activation in both pancreas and lung. Also, SC treatment further enhances the beneficial effect by reducing cerulein-induced mast cell activation as shown by reduced monocyte chemoattractant protein 1, interleukin 33, and preprotachykinin A expression (encodes neuropeptide substance P) in the pancreas and lungs. CONCLUSIONS The present findings show for the first time that in AP SC may exhibit an anti-inflammatory effect by down-regulating substance P and hydrogen sulfide signaling via nuclear factor κB pathway.
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Huang SJ, Yan JQ, Luo H, Zhou LY, Luo JG. IL-33/ST2 signaling contributes to radicular pain by modulating MAPK and NF-κB activation and inflammatory mediator expression in the spinal cord in rat models of noncompressive lumber disk herniation. J Neuroinflammation 2018; 15:12. [PMID: 29329586 PMCID: PMC5766999 DOI: 10.1186/s12974-017-1021-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 12/05/2017] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Immune and inflammatory responses occurring in the spinal cord play a pivotal role in the progression of radicular pain caused by intervertebral disk herniation. Interleukin-33 (IL-33) orchestrates inflammatory responses in a wide range of inflammatory and autoimmune disorders of the nervous system. Thus, the purpose of this study is to investigate the expression of IL-33 and its receptor ST2 in the dorsal spinal cord and to elucidate whether the inhibition of spinal IL-33 expression significantly attenuates pain-related behaviors in rat models of noncompressive lumbar disc herniation. METHODS Lentiviral vectors encoding short hairpin RNAs that target IL-33 (LV-shIL-33) were constructed for gene silencing. Rat models of noncompressive lumber disk herniation were established, and the spines of rats were injected with LV-shIL-33 (5 or 10 μl) on the first day after the operation. Mechanical thresholds were evaluated during an observation period of 21 days. Moreover, the expression levels of spinal tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase 2 (COX-2) and the activation of the mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated to gain insight into the mechanisms related to the contribution of IL-33/ST2 signaling to radicular pain. RESULTS The application of nucleus pulposus (NP) to the dorsal root ganglion (DRG) induced an increase in IL-33 and ST2 expression in the spinal cord, mainly in the dorsal horn neurons, astrocytes, and oligodendrocytes. Spinally delivered LV-shIL-33 knocked down the expression of IL-33 and markedly attenuated mechanical allodynia. In addition, spinal administration of LV-shIL-33 reduced the overexpression of spinal IL-1β, TNF-α, and COX-2 and attenuated the activation of C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and NF-κB/p65 but not p38. CONCLUSIONS This study indicates that spinal IL-33/ST2 signaling plays an important role in the development and progression of radicular pain in rat models of noncompressive lumber disk herniation. Thus, the inhibition of spinal IL-33 expression may provide a potential treatment to manage radicular pain caused by intervertebral disk herniation.
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Affiliation(s)
- Si-Jian Huang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China
| | - Jian-Qin Yan
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 China
| | - Hui Luo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 China
| | - Lu-Yao Zhou
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 China
| | - Jian-Gang Luo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 China
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Yamaya M, Nomura K, Arakawa K, Sugawara M, Deng X, Lusamba Kalonji N, Nishimura H, Yamada M, Nagatomi R, Kawase T. Clarithromycin decreases rhinovirus replication and cytokine production in nasal epithelial cells from subjects with bronchial asthma: effects on IL-6, IL-8 and IL-33. Arch Pharm Res 2017; 43:526-539. [PMID: 28861755 DOI: 10.1007/s12272-017-0950-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 08/21/2017] [Indexed: 01/17/2023]
Abstract
Rhinoviral infection is associated with an increased risk of asthma attacks. The macrolide clarithromycin decreases cytokine production in nasopharyngeal aspirates from patients with wheezing, but the effects of macrolides on cytokine production in nasal epithelial cells obtained from asthmatic subjects remain unclear. Here, human nasal epithelial cells were infected with type-14 rhinovirus (RV14), a major RV group. Titers and RNA of RV14 and cytokine concentrations, including IL-1β and IL-6, were higher in the supernatants of the cells obtained from subjects with bronchial asthma (asthmatic group) than in those from the non-asthmatic group. Pretreatment with clarithromycin decreased RV14 titers, viral RNA and cytokine concentrations, and susceptibility to RV14 infection. Pretreatment with clarithromycin also decreased IL-33 production, which was detected after infection. Pretreatment with clarithromycin decreased the expression of intercellular adhesion molecule-1, the receptor for RV14, after infection, the number and fluorescence intensity of the acidic endosomes through which RV RNA enters the cytoplasm, and the activation of nuclear factor kappa-B proteins in nuclear extracts. These findings suggested that RV replication and cytokine production may be enhanced in nasal epithelial cells obtained from subjects with bronchial asthma and may be modulated by clarithromycin.
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Affiliation(s)
- Mutsuo Yamaya
- Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Kazuhiro Nomura
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Kazuya Arakawa
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Mitsuru Sugawara
- Department of Otolaryngology, Tohoku Kosai Hospital, Sendai, 980-0803, Japan
| | - Xue Deng
- Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan
| | - Nadine Lusamba Kalonji
- Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan
| | - Hidekazu Nishimura
- Virus Research Center, Clinical Research Division, Sendai National Hospital, Sendai, 983-8520, Japan
| | - Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Ryoichi Nagatomi
- Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Tetsuaki Kawase
- Laboratory of Rehabilitative Auditory Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, 980-8575, Japan
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Conti P, Lessiani G, Kritas SK, Ronconi G, Caraffa A, Theoharides TC. Mast cells emerge as mediators of atherosclerosis: Special emphasis on IL-37 inhibition. Tissue Cell 2017; 49:393-400. [PMID: 28420489 DOI: 10.1016/j.tice.2017.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 04/10/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023]
Abstract
In atherosclerosis lipoproteins stimulate the innate immune response, leading to the release of inflammatory cytokines and chemokines. Hypercholesterolemia may activate the synthesis and release of inflammatory cytokines such as IL-1, which induces TNF release in mast cells (MCs). IL-1 and IL-1 family members orchestrate a broadening list of inflammatory diseases, including atherosclerosis. MCs are implicated in the pathophysiology of several diseases including allergy and inflammation. Activated MCs, located perivascularly, contribute to inflammation in atherosclerosis by producing inflammatory cytokines. MC IL-1-activation leads to the immediate release of inflammatory chemical mediators and TNF, and late inflammatory compounds such as cytokines. MCs can be activated by exogenous cytokines, antigens, microbial products (LPS) and neurotransmitters and generate IL-1 beta, TNF and several other inflammatory cytokines/chemokines along with PGD2, leukotrienes, histamine and proteases. MCs activated with IL-1 induce selective release of IL-6 without degranulation. TNF emerges as one of the most potent inflammatory cytokines involved in the response due to LDL. Cytokines, such as IL-1, IL-6, IL-33 and TNF, are generated in the inflammatory sites by both macrophages and MCs, mediating atherosclerosis. IL-37 (IL-1 family member 7) binds IL-18Ra chain and acts by an intracellular mechanism down-regulating the expression of pro-inflammatory signals cJun, MAP kinase p38a, STAT transcription factors and p53. Blocking IL-1 with IL-37 alleviates the symptoms in patients with inflammatory diseases including arteriosclerosis. The impact of IL-37 on inflammatory cytokines mediating atherosclerosis is beneficial and protective. However, more studies are needed to better define this mechanism and the safety and tolerability of IL-37.
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Affiliation(s)
- Pio Conti
- Immunology Division, Postgraduate Medical School, University of Chieti-Pescara, Viale Unità dell'Italia 73, 66013, Chieti, Italy.
| | - Gianfranco Lessiani
- Angiology Unit, Medicine and Geriatria, Villa Serena Hospital, Città Sant'Angelo, Italy
| | | | - Gianpaolo Ronconi
- Clinica dei Pazienti del Territorio, Policlinico Gemelli, Roma, Italy
| | | | - Theoharis C Theoharides
- Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
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Immunopathogenesis of pancreatitis. Mucosal Immunol 2017; 10:283-298. [PMID: 27848953 DOI: 10.1038/mi.2016.101] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 10/06/2016] [Indexed: 02/04/2023]
Abstract
The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic- or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstream induction of T cells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.
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Manohar M, Verma AK, Venkateshaiah SU, Sanders NL, Mishra A. Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 2017; 8:10-25. [PMID: 28217371 PMCID: PMC5292603 DOI: 10.4292/wjgpt.v8.i1.10] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/23/2016] [Accepted: 08/16/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.
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Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis. Mucosal Immunol 2016; 9:1234-49. [PMID: 26813347 DOI: 10.1038/mi.2015.144] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 12/05/2015] [Indexed: 02/04/2023]
Abstract
Nucleotide-binding oligomerization domain 1 (NOD1) fulfills important host-defense functions via its responses to a variety of gut pathogens. Recently, however, we showed that in acute pancreatitis caused by administration of cholecystokinin receptor (CCKR) agonist (cerulein) NOD1 also has a role in inflammation via its responses to gut commensal organisms. In the present study, we explored the long-term outcome of such NOD1 responsiveness in a new model of chronic pancreatitis induced by repeated administration of low doses of cerulein in combination with NOD1 ligand. We found that the development of chronic pancreatitis in this model requires intact NOD1 and type I IFN signaling and that such signaling mediates a macrophage-mediated inflammatory response that supports interleukin (IL)-33 production by acinar cells. The IL-33, in turn, has a necessary role in the induction of IL-13 and TGF-β1, factors causing the fibrotic reaction characteristic of chronic pancreatitis. Interestingly, the Th2 effects of IL-33 were attenuated by the concomitant type I IFN response since the inflammation was marked by clear increases in IFN-γ and TNF-α production but only marginal increases in IL-4 production. These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways.
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Allan D, Fairlie-Clarke KJ, Elliott C, Schuh C, Barnett SC, Lassmann H, Linnington C, Jiang HR. Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system. Acta Neuropathol Commun 2016; 4:75. [PMID: 27455844 PMCID: PMC4960877 DOI: 10.1186/s40478-016-0344-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 07/06/2016] [Indexed: 12/15/2022] Open
Abstract
Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer's disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination.
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Schnúr A, Hegyi P, Rousseau S, Lukacs GL, Veit G. Epithelial Anion Transport as Modulator of Chemokine Signaling. Mediators Inflamm 2016; 2016:7596531. [PMID: 27382190 PMCID: PMC4921137 DOI: 10.1155/2016/7596531] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 05/03/2016] [Accepted: 05/12/2016] [Indexed: 12/16/2022] Open
Abstract
The pivotal role of epithelial cells is to secrete and absorb ions and water in order to allow the formation of a luminal fluid compartment that is fundamental for the epithelial function as a barrier against environmental factors. Importantly, epithelial cells also take part in the innate immune system. As a first line of defense they detect pathogens and react by secreting and responding to chemokines and cytokines, thus aggravating immune responses or resolving inflammatory states. Loss of epithelial anion transport is well documented in a variety of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, pancreatitis, and cholestatic liver disease. Here we review the effect of aberrant anion secretion with focus on the release of inflammatory mediators by epithelial cells and discuss putative mechanisms linking these transport defects to the augmented epithelial release of chemokines and cytokines. These mechanisms may contribute to the excessive and persistent inflammation in many respiratory and gastrointestinal diseases.
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Affiliation(s)
- Andrea Schnúr
- Department of Physiology, McGill University, Montréal, QC, Canada H3G 1Y6
| | - Péter Hegyi
- Institute for Translational Medicine and 1st Department of Medicine, University of Pécs, Pécs 7624, Hungary
- MTA-SZTE Translational Gastroenterology Research Group, Szeged 6720, Hungary
| | - Simon Rousseau
- The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montréal, QC, Canada H2X 2P2
| | - Gergely L. Lukacs
- Department of Physiology, McGill University, Montréal, QC, Canada H3G 1Y6
- Department of Biochemistry, McGill University, Montréal, QC, Canada H3G 1Y6
- Groupe de Recherche Axé sur la Structure des Protéines (GRASP), McGill University, Montréal, QC, Canada H3G 1Y6
| | - Guido Veit
- Department of Physiology, McGill University, Montréal, QC, Canada H3G 1Y6
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Jakkampudi A, Jangala R, Reddy BR, Mitnala S, Nageshwar Reddy D, Talukdar R. NF-κB in acute pancreatitis: Mechanisms and therapeutic potential. Pancreatology 2016; 16:477-88. [PMID: 27282980 DOI: 10.1016/j.pan.2016.05.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 05/03/2016] [Accepted: 05/04/2016] [Indexed: 12/11/2022]
Abstract
The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies. Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.
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Affiliation(s)
- Aparna Jakkampudi
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - Ramaiah Jangala
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - B Ratnakar Reddy
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - Sasikala Mitnala
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India
| | - D Nageshwar Reddy
- Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Rupjyoti Talukdar
- Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India; Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
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Tsai WH, Wu CH, Yu HJ, Chien CT. l-Theanine inhibits proinflammatory PKC/ERK/ICAM-1/IL-33 signaling, apoptosis, and autophagy formation in substance P-induced hyperactive bladder in rats. Neurourol Urodyn 2016; 36:297-307. [PMID: 26828717 DOI: 10.1002/nau.22965] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 01/15/2016] [Indexed: 12/13/2022]
Abstract
AIMS Upregulation of substance P (SP) and neurokinin-1 receptor (NK1R) activation induces pro-inflammatory bladder hyperactivity through the PKC/ERK/NF-κB/ICAM-1/IL-33 signaling pathways to increase the leukocyte infiltration and adhesion leading to reactive oxygen species (ROS) production, autophagy, and apoptosis. l-Theanine is a unique non-protein-forming amino acid present in tea (Camellia sinensis [L.] O. Kuntze) with its antioxidant, anti-inflammatory, and relaxation effects to improve cognition, mood, gastric ulcer injury, and cerebral ischemia/reperfusion injury, and posttraumatic stress disorder. We explored the protective effect of l-theanine on SP-induced bladder hyperactivity. METHODS In urethane-anesthetized female Wistar rats, we explored the transcystometrogram, pelvic nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, apoptosis-related Caspase 3/poly-(ADP-ribose)-polymerase (PARP), and autophagy-mediated LC3 II expression by Western blot, electrophoretic-mobility shift assay and immunohistochemistry, bladder ROS amount by a ultrasensitive chemiluminescence method, and possible ROS sources from the different leukocytes by specific stains in SP-evoked hyperactive bladder. RESULTS l-Theanine dose-dependently depressed H2 O2 and HOCl activity in vitro. In urethane-anesthetized female Wistar rats, intra-arterial SP through NK1R activation increased voiding frequency (shortened intercontraction intervals) associated with the increase in bladder nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, Caspase 3/PARP-mediated apoptosis, LC3 II-mediated autophagy, ROS amount, neutrophils adhesion, CD68 (monocyte/macrophage) infiltration, and mast cells degranulation in the hyperactive bladder. Intragastrical l-theanine (15 mg/kg) twice daily for 2 weeks efficiently ameliorated all the enhanced parameters in the SP-treated hyperactive bladder. CONCLUSIONS In conclusion, l-theanine through antioxidant and anti-inflammatory actions ameliorates SP-induced bladder hyperactivity via the inhibition of proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, oxidative stress, bladder nerve hyperactivity, apoptosis, and autophagy. Neurourol. Urodynam. 36:297-307, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Wen-Hsin Tsai
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.,Department of Traditional Chinese Medicine, Taipei City Hospital Linsen (Chinese Medicine) Branch, Taipei, Taiwan
| | - Chung-Hsin Wu
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Hong-Jeng Yu
- Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chiang-Ting Chien
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
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Shamoon M, Deng Y, Chen YQ, Bhatia M, Sun J. Therapeutic implications of innate immune system in acute pancreatitis. Expert Opin Ther Targets 2015; 20:73-87. [PMID: 26565751 DOI: 10.1517/14728222.2015.1077227] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Acute pancreatitis (AP) is an inflammatory disorder of the pancreas encompassing a cascade of cellular and molecular events. It starts from premature activation of zymogens with the involvement of innate immune system to a potential systemic inflammatory response and multiple organ failure. Leukocytes are the major cell population that participate in the propagation of the disease. Current understanding of the course of AP is still far from complete, limiting treatment options mostly to conservative supportive care. Emerging evidence has pointed to modulation of the immune system for strategic therapeutic development, by mitigating the inflammatory response and severity of AP. In the current review, we have focused on the role of innate immunity in the condition and highlighted therapeutics targeting it for treatment of this challenging disease. AREAS COVERED The current review has aimed to elaborate in-depth understanding of specific roles of innate immune cells, derived mediators and inflammatory pathways that are involved in AP. Summarizing the recent therapeutics and approaches applied experimentally that target immune responses to attenuate AP. EXPERT OPINION The current state of knowledge on AP, limitations of presently available therapeutic approaches and the promise of therapeutic implications of innate immune system in AP are discussed.
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Affiliation(s)
- Muhammad Shamoon
- a 1 Jiangnan University, School of Food Science and Technology, The Synergetic Innovation Center of Food Safety and Nutrition, State Key Laboratory of Food Science and Technology , Wuxi, Jiangsu, China
| | - Yuanyuan Deng
- a 1 Jiangnan University, School of Food Science and Technology, The Synergetic Innovation Center of Food Safety and Nutrition, State Key Laboratory of Food Science and Technology , Wuxi, Jiangsu, China
| | - Yong Q Chen
- a 1 Jiangnan University, School of Food Science and Technology, The Synergetic Innovation Center of Food Safety and Nutrition, State Key Laboratory of Food Science and Technology , Wuxi, Jiangsu, China
| | - Madhav Bhatia
- b 2 University of Otago, Inflammation Research Group, Department of Pathology , Christchurch, 2 Riccarton Avenue, P.O. Box 4345, Christchurch 8140, New Zealand
| | - Jia Sun
- a 1 Jiangnan University, School of Food Science and Technology, The Synergetic Innovation Center of Food Safety and Nutrition, State Key Laboratory of Food Science and Technology , Wuxi, Jiangsu, China
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Fan YT, Yin GJ, Xiao WQ, Qiu L, Yu G, Hu YL, Xing M, Wu DQ, Cang XF, Wan R, Wang XP, Hu GY. Rosmarinic Acid Attenuates Sodium Taurocholate-Induced Acute Pancreatitis in Rats by Inhibiting Nuclear Factor-κB Activation. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2015; 43:1117-35. [PMID: 26364660 DOI: 10.1142/s0192415x15500640] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Rosmarinic Acid (RA), a caffeic acid ester, has been shown to exert anti-inflammation, anti-oxidant and antiallergic effects. Our study aimed to investigate the effect of RA in sodium taurocholate ( NaTC )-induced acute pancreatitis, both in vivo and in vitro. In vivo, RA (50 mg/kg) was administered intraperitoneally 2 h before sodium taurocholate injection. Rats were sacrificed 12 h, 24 h or 48 h after sodium taurocholate injection. Pretreatment with RA significantly ameliorated pancreas histopathological changes, decreased amylase and lipase activities in serum, lowered myeloperoxidase activity in the pancreas, reduced systematic and pancreatic interleukin-1 β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) levels, and inhibited NF-κB translocation in pancreas. In vitro, pretreating the fresh rat pancreatic acinar cells with 80 μ mol/L RA 2 h before 3750 nmol/L sodium taurocholate or 10 ng/L TNF-α administration significantly attenuated the reduction of isolated pancreatic acinar cell viability and inhibited the nuclear activation and translocation of NF-κB. Based on our findings, RA appears to attenuate damage in sodium taurocholate-induced acute pancreatitis and reduce the release of inflammatory cytokines by inhibiting the activation of NF-κB. These findings might provide a basis for investigating the therapeutic role of RA in managing acute pancreatits.
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Affiliation(s)
- Yu-Ting Fan
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Guo-Jian Yin
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Wen-Qin Xiao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Lei Qiu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ge Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yan-Ling Hu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Miao Xing
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - De-Qing Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xiao-Feng Cang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Xing-Peng Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Guo-Yong Hu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
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Abstract
PURPOSE OF REVIEW This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis. RECENT FINDINGS Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation. SUMMARY Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.
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Hoque R, Mehal WZ. Inflammasomes in pancreatic physiology and disease. Am J Physiol Gastrointest Liver Physiol 2015; 308:G643-51. [PMID: 25700081 PMCID: PMC4398840 DOI: 10.1152/ajpgi.00388.2014] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 02/10/2015] [Indexed: 01/31/2023]
Abstract
In this review we summarize the role of inflammasomes in pancreatic physiology and disease with a focus on acute pancreatitis where much recent progress has been made. New findings have identified inducers of and cell specificity of inflammasome component expression in the pancreas, the contribution of inflammasome-regulated effectors to pancreatitis, and metabolic regulation of inflammasome activation, which are strong determinants of injury in pancreatitis. New areas of pancreatic biology will be highlighted in the context of our evolving understanding of gut microbiome- and injury-induced inflammasome priming, pyroptosis, and innate immune-mediated regulation of cell metabolism.
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Affiliation(s)
- Rafaz Hoque
- 1Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; and
| | - Wajahat Z. Mehal
- 1Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; and ,2Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut
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Funakoshi-Tago M, Okamoto K, Izumi R, Tago K, Yanagisawa K, Narukawa Y, Kiuchi F, Kasahara T, Tamura H. Anti-inflammatory activity of flavonoids in Nepalese propolis is attributed to inhibition of the IL-33 signaling pathway. Int Immunopharmacol 2015; 25:189-98. [PMID: 25614224 DOI: 10.1016/j.intimp.2015.01.012] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 12/23/2014] [Accepted: 01/12/2015] [Indexed: 12/16/2022]
Abstract
Propolis has been used in folk medicine to improve health and prevent inflammatory diseases; however, the components that exhibit its anti-inflammatory activity remain unknown. We herein investigated the effects of flavonoids isolated from Nepalese propolis on the IL-33 signaling pathway to clarify the anti-inflammatory mechanism involved. Of the 8 types of flavonoids isolated from Nepalese propolis, 4 types of compounds, such as 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, cearoin, and chrysin, markedly inhibited the IL-33-induced mRNA expression of inflammatory genes including IL-6, TNFα and IL-13 in bone marrow-derived mast cells (BMMC). These four flavonoids also inhibited the IL-33-induced activation of nuclear factor κB (NF-κB), which was consistent with their inhibitory effects on cytokine expression. The effects of these flavonoids are attributed to inhibition of IL-33-induced activation of IKK, which leads to the degradation of IκBα and nuclear localization of NF-κB. On the other hand, other flavonoids isolated from Nepalese propolis, such as isoliquiritigenin, plathymenin, 7-hydroxyflavanone, and (+)-medicarpin, had no effect on the IL-33 signaling pathway or cytokine expression. Therefore, these results indicate that 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, cearoin, and chrysin are the substances responsible for the anti-inflammatory activity of Nepalese propolis.
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Affiliation(s)
- Megumi Funakoshi-Tago
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
| | - Kazuhi Okamoto
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Rika Izumi
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Kenji Tago
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, 329-0498 Tochigi, Japan
| | - Ken Yanagisawa
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, 329-0498 Tochigi, Japan
| | - Yuji Narukawa
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Fumiyuki Kiuchi
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Tadashi Kasahara
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Hiroomi Tamura
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
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Abstract
Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.
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Zheng YQ, Huang J, Zeng FC, Zhou XY. Application of caerulein and lipopolysaccharides in creating mouse models of mild or severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2014; 22:4068-4074. [DOI: 10.11569/wcjd.v22.i27.4068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish typical mouse models of mild or severe acute pancreatitis induced with caerulein (CAE) and/or lipopolysaccharides (LPS).
METHODS: Fifty healthy adult male C57 mice were randomly divided into five groups (with 10 mice in each group): a control group (CON group), the caerulein 7 group (CAE 7 group), a caerulein 7 plus LPS group (CAE 7 + LPS group), a caerulein 13 group (CAE 13 group), and a caerulein 13 plus LPS group (CAE 13 + LPS group). All the animals were killed three hours after the last intraperitoneal injection. The pancreas was carefully removed for microscopic examination and further observed under a transmission electron microscope (TEM). Serum amylase and lipase concentrations were assayed.
RESULTS: Enzyme levels and pathological score in all the experimental groups were significantly higher than those in the CON group (amylase lowest CAE 7 group: 27020 U/dL ± 3443 U/dL vs CON group: 2696 U/dL ± 400 U/dL, P < 0.01; lipase content lowest CAE 7 group: 1379 U/L ± 283 U/L vs CON group: 33 U/L ± 13 U/L, P < 0.01; pathological score lowest CAE 7 group: 5.8 ± 0.9 vs CON group: 0.1 ± 0.3, P < 0.01). Compared with the CAE 7 group, the enzyme levels and pathological score in the CAE 13 + LPS group increased more significantly (CAE 13 + LPS group amylase: 46969 U/dL ± 11852 U/dL vs CAE 7 group amylase: 27020 U/dL ± 3443 U/dL, P < 0.01; CAE13 + LPS group lipase: 1962 U/dL ± 496 U/dL vs CAE 7 group lipase: 1379 U/dL ± 283 U/dL, P < 0.05; CAE13 + LPS group pathological score : 11.1 ± 1.1 vs CAE 7 group pathological score : 5.8 ± 0.9, P < 0.05). The grade of pathological changes in the CAE 13 + LPS group was significantly higher than that in the CAE 13 group (CAE 13 + LPS group: 11.1 ± 1.1 vs CAE 13 group: 10.1 ± 0.99, P < 0.05). The ultrastructure of acinar cells was damaged in the CAE 7 group, and the rough endoplasmic reticulum and mitochondria were markedly swollen. However, in the CAE 13 + LPS group, the acinar cells were seriously damaged.
CONCLUSION: Caerulein alone by intraperitoneal injection 7 times can be used to prepare a typical model of acute edematous pancreatitis, and caerulein by intraperitoneal injection 13 times plus LPS at the last time can be used to produce typical acute necrotizing pancreatitis.
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Induction of m2 polarization in primary culture liver macrophages from rats with acute pancreatitis. PLoS One 2014; 9:e108014. [PMID: 25259888 PMCID: PMC4178066 DOI: 10.1371/journal.pone.0108014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Accepted: 08/24/2014] [Indexed: 12/15/2022] Open
Abstract
Background and Aims Systemic inflammatory response syndrome (SIRS), a major process of severe acute pancreatitis (SAP), usually occurs after various activated proinflammatory cytokines, which are produced by macrophages such as liver macrophages. Macrophages can secrete not only proinflammatory mediators but also inhibitory inflammatory cytokines such as IL-10, leading to two different functional states defined as “polarization”. The main purpose of this study was to demonstrate the polarization of liver macrophages during severe acute pancreatitis and to explore whether the polarization of these activated Liver macrophages could be reversed in vitro. Methods Liver macrophages were isolated from rats with acute pancreatitis. These primary culture macrophages were treated with IL-4 or regulatory T cells in vitro to reverse their polarization and was evaluated by measuring M1/M2 marker expression using real time PCR and immunofluorescence staining. Results Acute pancreatitis was induced successfully by intra-pancreatic ductal injection of 5% sodium taurocholate. The liver macrophages demonstrated M1 polarization from 4 h to 16 h after the onset of acute pancreatitis. However, after IL-4 or Treg treatment, the polarization of the liver macrophages was reversed as indicated by increased expression of M2 markers and reduced expression of M1 markers. Furthermore, the effect of Treg on modulating macrophage polarization was slightly better than that of IL-4 in vitro. Conclusion Liver macrophages, a pivotal cell type in the pathogenesis of SAP, become M1 polarized during pancreatic inflammation. Treatment of these cells with IL-4 and Treg can reverse this activation in vitro. This method of altering macrophage polarization could be a prospective therapy for SAP.
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Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol 2014; 20:11160-11181. [PMID: 25170202 PMCID: PMC4145756 DOI: 10.3748/wjg.v20.i32.11160] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/27/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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