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Treppiccione L, Maurano F, Rossi S, Luongo D, Rossi M. Transamidated wheat gliadin induces differential antigen recognition in the small intestine of HLA/DQ8 transgenic mice. Food Funct 2022; 13:8941-8950. [PMID: 35929785 DOI: 10.1039/d2fo02032g] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A lifelong gluten-free diet (GFD) is currently the only available therapy for coeliac disease (CD). However, GFD compliance is difficult and alternative strategies are envisaged in the near future. We previously found that wheat gliadin following transamidation by microbial transglutaminase (mTG) does not induce IFN-γ secretion by intestinal T cells from CD patients. Fully transamidated gliadin with lysine ethyl ester can be recovered in a soluble protein fraction (spf) generated by the enzymatic treatment of wheat flour. Herein, we analysed the performance of transamidation by mTG on a pilot-scale (1L) by evaluating the reaction kinetics and its biological effect on the intestinal immune response in HLA/DQ8 transgenic mice, a model of gluten sensitivity. At 1 h, all gliadin fractions showed a faster electrophoretic mobility by acid-polyacrylamide gel electrophoresis (A-PAGE) following transamidation in comparison with their native counterparts. In parallel, the yield of residual native gliadin dropped (30% at 180 min), confirming our previous findings on a lab scale. Mucosal sensitisation of mice with gliadin via the intranasal route induced a Th1 phenotype in mesenteric lymph nodes (MLNs). Importantly, IFN-γ secretion was significantly reduced when gliadin-specific MLN cells were challenged in vitro with spf (P < 0.001). Multiplex analysis revealed that the adaptive immune response evoked by spf involved a distinct cell population characterised by secretion of IL-2, IL-3 and IL-5. Notably, spf stimulated in vitro a reduced or null secretion of all of the examined pro-inflammatory markers mainly associated to innate immunity. In conclusion, our data revealed the ability of transamidated gliadin to modulate both innate and adaptive mechanisms involved in the inflammatory response induced by wheat gliadin in the small intestine of DQ8 mice.
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Affiliation(s)
| | - Francesco Maurano
- Institute of Food Sciences, National Research Council, Avellino, Italy.
| | - Stefano Rossi
- Institute of Food Sciences, National Research Council, Avellino, Italy.
| | - Diomira Luongo
- Institute of Food Sciences, National Research Council, Avellino, Italy.
| | - Mauro Rossi
- Institute of Food Sciences, National Research Council, Avellino, Italy.
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2
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Knapp MPA, Johnson TA, Ritter MK, Rainer RO, Fiester SE, Grier JT, Connell TD, Arce S. Immunomodulatory regulation by heat-labile enterotoxins and potential therapeutic applications. Expert Rev Vaccines 2021; 20:975-987. [PMID: 34148503 DOI: 10.1080/14760584.2021.1945449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Introduction: Heat-labile enterotoxins (HLTs) and their cognate ganglioside receptors have been extensively studied because of their therapeutic potential. Gangliosides play arole in modulating effector cells of the immune system, and HLTs provide a novel means for stimulating ganglioside-mediated responses in immunocompetent cells.Areas covered: To evaluate the mechanisms of HLT adjuvanticity, a systemic literature review was performed using relevant keyword searches of the PubMed database, accessing literature published as recently as late 2020. Since HLTs bind to specific ganglioside receptors on immunocytes, they can act as regulators via stimulation or tapering of immune responses from associated signal transduction events. Binding of HLTs to gangliosides can increase proliferation of T-cells, increase cytokine release, augment mucosal/systemic antibody responses, and increase the effectiveness of antigen presenting cells. Subunit components also independently stimulate certain immune responses. Mutant forms of HLTs have potent immunomodulatory effects without the toxicity associated with holotoxins.Expert opinion: HLTs have been the subject of abundant research exploring their use as vaccine adjuvants, in the treatment of autoimmune conditions, in cancer therapy, and for weight loss, proving that these molecules are promising tools in the field of immunotherapy.
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Affiliation(s)
- Mary-Peyton A Knapp
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA
| | - Taylor A Johnson
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA
| | - Madison K Ritter
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA
| | - Robert O Rainer
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA.,Prisma Health, Department of Pathology, Greenville, SC, USA
| | - Steven E Fiester
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA.,Prisma Health, Department of Pathology, Greenville, SC, USA
| | - Jennifer T Grier
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA
| | - Terry D Connell
- University of Buffalo, Jacobs School of Medicine and Biomedical Sciences and the Witebsky Center of Microbial Pathogenesis and Immunology, Buffalo, NY, USA
| | - Sergio Arce
- University of South Carolina School of Medicine Greenville, Department of Biomedical Sciences, Greenville, SC, USA.,Prisma Health, Cancer Institute, Greenville, SC, USA
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Rossi S, Giordano D, Mazzeo MF, Maurano F, Luongo D, Facchiano A, Siciliano RA, Rossi M. Transamidation Down-Regulates Intestinal Immunity of Recombinant α-Gliadin in HLA-DQ8 Transgenic Mice. Int J Mol Sci 2021; 22:ijms22137019. [PMID: 34209932 PMCID: PMC8268696 DOI: 10.3390/ijms22137019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 11/21/2022] Open
Abstract
Enzymatic transamidation of gliadins by microbial transglutaminase (mTG) inhibits interferon-γ (IFN-γ) secretion by intestinal T cell lines in patients with celiac disease (CD). To gain insight into the cellular mechanisms underlying the down-regulatory effects of transamidation, we tested a single recombinant α-gliadin (r-gliadin) harbouring two immunodominant peptides, p13 (aa. 120–139) and p23 (aa. 220–239), in HLA-DQ8 transgenic mice, a model of gluten sensitivity. Mice were intranasally immunised with r-gliadin or r-gliadin transamidated by mTG (K-r-gliadin) along with cholera toxin, and the response of mesenteric lymph node cells was analysed by cytokine multiplex assay. An in vitro challenge with r-gliadin was characterised by secretion of specific cytokines featuring both innate immunity and the Th1/Th2/Th17 pattern of the adaptive response. Notably, transamidation specifically down-regulated the Th1 response. Structural studies performed on K-r-gliadin confirmed that specific glutamine residues in p13 and p23, previously found to be deamidated by tissue transglutaminase, were also transamidated by mTG. In silico analysis, simulating p13 and p23 peptide binding to HLA-DQ8 showed that these glutamines, in the form of glutamate, could interact by means of salt bridges with peculiar amino acids of the alpha chain of HLA-DQ8, suggesting that their transamidation may influence the HLA-restricted recognition of these peptides. Thus, the structural findings provided a rationale to explain the down-regulation of the r-gliadin-specific Th1 response following transamidation.
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Affiliation(s)
- Stefano Rossi
- Immunobiology Unit, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (S.R.); (F.M.); (D.L.)
| | - Deborah Giordano
- Bioinformatics and Computational Biology Unit, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (D.G.); (A.F.)
| | - Maria Fiorella Mazzeo
- Proteomics and Biomolecular Mass Spectrometry Center, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (M.F.M.); (R.A.S.)
| | - Francesco Maurano
- Immunobiology Unit, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (S.R.); (F.M.); (D.L.)
| | - Diomira Luongo
- Immunobiology Unit, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (S.R.); (F.M.); (D.L.)
| | - Angelo Facchiano
- Bioinformatics and Computational Biology Unit, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (D.G.); (A.F.)
| | - Rosa Anna Siciliano
- Proteomics and Biomolecular Mass Spectrometry Center, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (M.F.M.); (R.A.S.)
| | - Mauro Rossi
- Immunobiology Unit, CNR, Institute of Food Sciences, 83100 Avellino, Italy; (S.R.); (F.M.); (D.L.)
- Correspondence: ; Tel.: +39-825-299371
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You RI, Lee YP, Su TY, Lin CC, Chen CS, Chu CL. A Benzenoid 4,7-Dimethoxy-5-Methyl-L, 3-Benzodioxole from Antrodia cinnamomea Attenuates Dendritic Cell-Mediated Th2 Allergic Responses. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:1271-1287. [PMID: 31488035 DOI: 10.1142/s0192415x19500654] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dendritic cells (DCs) play a critical role in initiating immune responses; however, DCs also induce Th2-related allergic sensitivities. Thus, DCs become a target for therapeutic design in allergic diseases. In this study, we aim to investigate the anti-allergic effect of pure compounds from a medicinal mushroom Antrodia cinnamomea (Ac) on DC-induced allergic responses. We identified a benzenoid compound 4,7-dimethoxy-5-methyl-l,3-benzodioxole (DMB) which may modulate Th2 polarization in bone marrow-derived DCs (BMDCs) and in a murine food allergy model. DMB effectively reduced the Th2 adjuvant cholera toxin (CT)-induced BMDC maturation and cytokine production. In studying the mechanism, DMB blocked the molecular processes involved in Th2 induction, including cAMP activation, IL-33 production, and IRF4/Tim4 upregulation, in CT-activated BMDCs. Furthermore, DMB treatment attenuated the symptoms, clinical scores, and Th2 responses of CT-induced ovalbumin (OVA)-specific food allergy in mice at sensitization stage. These results indicated that DMB could suppress DC function for Th2 polarization and mitigate allergic responses. Thus, DMB may have potential to be a novel agent for preventing or treating food allergy.
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Affiliation(s)
- Ren-In You
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan
| | - Yi-Pang Lee
- Department of Health Administration, Tzu Chi University of Science and Technology, Hualien, Taiwan.,Division of Oral Pathology, Department of Dentistry, Tzu Chi General Hospital, Hualien, Taiwan
| | - Ting-Yi Su
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Chien Lin
- Institute of Biomedical Sciences, National Chung Hsin University, Taichung, Taiwan
| | - Chang-Shan Chen
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan
| | - Ching-Liang Chu
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
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5
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Zaal A, van Ham SM, Ten Brinke A. Differential effects of anaphylatoxin C5a on antigen presenting cells, roles for C5aR1 and C5aR2. Immunol Lett 2019; 209:45-52. [PMID: 30959077 DOI: 10.1016/j.imlet.2019.03.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 12/24/2022]
Abstract
The anaphylatoxin C5a is well-known for its role as chemoattractant and contributes to immune cell recruitment into inflamed tissue and local inflammation. C5a has recently been implicated in modulation of antigen presenting cell function, such as macrophages and dendritic cells, which are pivotal for T cell activation and final T cell effector function. The published data on the effect of C5a on APC function and subsequent adaptive immune responses are in part conflicting, as both pro and anti-inflammatory effects have been described. In this review the opposing effects of C5a on APC function in mice and human are summarized and discussed in relation to origin of the involved APC subset, being either of the monocyte-derived lineage or dendritic cell lineage. In addition, the current knowledge on the expression of C5aR1 and C5aR2 on the different APC subsets is summarized. Based on the combined data, we propose that the differential effects of C5a on APC function may be attributed to absence or presence of co-expression of C5aR2 and C5aR1 on the specific APC.
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Affiliation(s)
- Anouk Zaal
- Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - S Marieke van Ham
- Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Swammerdam Institute for Life Sciences, University of Amsterdam, the Netherlands
| | - Anja Ten Brinke
- Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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6
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Vallejo AF, Read RC, Arevalo-Herrera M, Herrera S, Elliott T, Polak ME. Malaria systems immunology: Plasmodium vivax induces tolerance during primary infection through dysregulation of neutrophils and dendritic cells. J Infect 2018; 77:440-447. [PMID: 30248353 PMCID: PMC6203889 DOI: 10.1016/j.jinf.2018.09.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/14/2018] [Accepted: 09/15/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To dissect the transcriptional networks underpinning immune cells responses during primary Plasmodium vivax infection of healthy human adults. METHODS We conducted network co-expression analysis of next-generation RNA sequencing data from whole blood from P. vivax and P. falciparum controlled human malaria infection (CHMI) of healthy naïve and malaria-exposed volunteers. Single cell transcription signatures were used to deconvolute the bulk RNA-Seq data into cell-specific signals. RESULTS Initial exposure to P. vivax induced activation of innate immunity, including efficient antigen presentation and complement activation. However, this effect was accompanied by strong immunosuppression mediated by dendritic cells via the induction of Indoleamine 2,3-Dioxygenase 1(IDO1) and Lymphocyte Activation Gene 3 (LAG3). Additionally, P. vivax induced depletion of neutrophil populations associated with down regulation of 3G-protein coupled receptors, CRXCR1, CXCR2 and CSF3R. Accordingly, in malaria-exposed volunteers the inflammatory response was attenuated, with a decreased class II antigen presentation in dendritic cells. While the immunosuppressive signalling was maintained between plasmodium species, response to P. falciparum was significantly more immunogenic. CONCLUSIONS In silico analyses suggest that primary infection with P. vivax induces potent immunosuppression mediated by dendritic cells, conditioning subsequent anti-malarial immune responses. Targeting immune evasion mechanisms could be an effective alternative for improving vaccine efficacy.
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Affiliation(s)
- Andres F Vallejo
- Clinical and Experimental Sciences and NIHR Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, LE59, MP813, SO16 6YD, Southampton, UK
| | - Robert C Read
- Clinical and Experimental Sciences and NIHR Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, LE59, MP813, SO16 6YD, Southampton, UK
| | - Myriam Arevalo-Herrera
- Caucaseco Scientific Research Center, Cali, 760043, Colombia; School of Health, Universidad del Valle, Cali, 76001, Colombia
| | | | - Tim Elliott
- Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK; Institute for Life Sciences, University of Southampton, SO17 1BJ, UK
| | - Marta E Polak
- Clinical and Experimental Sciences and NIHR Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, LE59, MP813, SO16 6YD, Southampton, UK; Institute for Life Sciences, University of Southampton, SO17 1BJ, UK.
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7
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Probiotics SOD inhibited food allergy via downregulation of STAT6-TIM4 signaling on DCs. Mol Immunol 2018; 103:71-77. [PMID: 30216839 DOI: 10.1016/j.molimm.2018.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 09/03/2018] [Accepted: 09/04/2018] [Indexed: 12/16/2022]
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ADP-ribosylating enterotoxins as vaccine adjuvants. Curr Opin Pharmacol 2018; 41:42-51. [PMID: 29702466 DOI: 10.1016/j.coph.2018.03.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 03/30/2018] [Indexed: 01/18/2023]
Abstract
Most infections are caused by pathogens that access the body at mucosal sites. Hence, development of mucosal vaccines to prevent local infection or invasion of pathogens appears highly warranted, especially since only mucosal immunization will stimulate strong local IgA responses and tissue resident memory CD4 and CD8 T cells. The most significant obstacle to developing such vaccines is the lack of approved adjuvants that can effectively and safely enhance relevant mucosal and systemic immune responses. The most potent mucosal adjuvants known today are the adenosine diphosphate (ADP)-ribosylating bacterial enterotoxins cholera toxin (CT) and Escherichia coli heat-labile toxins (LTs). Unfortunately, these molecules are also very toxic, which precludes their clinical use. However, much effort has been devoted to developing derivatives of these enterotoxins with low or no toxicity and retained adjuvant activity. Although it is fair to say that we know more about how these toxins affect the immune system than ever before, we still lack a detailed understanding of how and why these toxins are effective adjuvants. In the present review, we provide a state-of-the-art overview of the mechanism of action of the holotoxins and the strategies used for improving the toxin-based adjuvants.
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Kuo CH, Yang SN, Tsai YG, Hsieh CC, Liao WT, Chen LC, Lee MS, Kuo HF, Lin CH, Hung CH. Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation. Pulm Pharmacol Ther 2017; 48:37-45. [PMID: 28987803 DOI: 10.1016/j.pupt.2017.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 10/01/2017] [Accepted: 10/03/2017] [Indexed: 01/01/2023]
Abstract
The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca2+ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β2-adrenoreceptor-cAMP-Epac-Ca2+, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.
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Affiliation(s)
- Chang-Hung Kuo
- Ta-Kuo Clinic, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - San-Nan Yang
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Yi-Giien Tsai
- Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chong-Chao Hsieh
- Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wei-Ting Liao
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Li-Chen Chen
- The Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Min-Sheng Lee
- Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsuan-Fu Kuo
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Ching-Hsiung Lin
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Chest Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Hsing Hung
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Rossato M, Affandi AJ, Thordardottir S, Wichers CGK, Cossu M, Broen JCA, Moret FM, Bossini-Castillo L, Chouri E, van Bon L, Wolters F, Marut W, van der Kroef M, Silva-Cardoso S, Bekker CPJ, Dolstra H, van Laar JM, Martin J, van Roon JAG, Reedquist KA, Beretta L, Radstake TRDJ. Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis. Arthritis Rheumatol 2017; 69:1891-1902. [PMID: 28556560 DOI: 10.1002/art.40163] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 05/23/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Plasmacytoid dendritic cells (PDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to PDC dysregulation and a persistent type I IFN signature are largely unexplored, especially in patients with systemic sclerosis (SSc), a disease in which PDCs infiltrate fibrotic skin lesions and produce higher levels of IFNα than those in healthy controls. This study was undertaken to investigate potential microRNA (miRNA)-mediated epigenetic mechanisms underlying PDC dysregulation and type I IFN production in SSc. METHODS We performed miRNA expression profiling and validation in highly purified PDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miRNA-618 (miR-618) on PDC biology were identified by overexpression in healthy PDCs. RESULTS Expression of miR-618 was up-regulated in PDCs from SSc patients, including those with early disease who did not present with skin fibrosis. IFN regulatory factor 8, a crucial transcription factor for PDC development and activation, was identified as a target of miR-618. Overexpression of miR-618 reduced the development of PDCs from CD34+ cells in vitro and enhanced their ability to secrete IFNα, mimicking the PDC phenotype observed in SSc patients. CONCLUSION Up-regulation of miR-618 suppresses the development of PDCs and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of PDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.
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Affiliation(s)
- Marzia Rossato
- University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | | | - Marta Cossu
- University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | - Lara Bossini-Castillo
- Consejo Superior de Investigaciones Científicas, Granada, Spain, and Wellcome Trust Sanger Institute, Cambridge, UK
| | - Eleni Chouri
- University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lenny van Bon
- University Medical Center Utrecht, Utrecht, The Netherlands
| | - Femke Wolters
- University Medical Center Utrecht, Utrecht, The Netherlands
| | - Wioleta Marut
- University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | | | - Harry Dolstra
- Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Javier Martin
- Consejo Superior de Investigaciones Científicas, Granada, Spain
| | | | | | - Lorenzo Beretta
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
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11
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Rossi S, Luongo D, Maurano F, Bergamo P, Rossi M. Immunomodulatory activity of recombinant α-gliadin conjugated to cholera toxin in DQ8 transgenic mice. Immunol Lett 2017; 187:47-52. [PMID: 28511837 DOI: 10.1016/j.imlet.2017.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/23/2017] [Accepted: 05/05/2017] [Indexed: 01/29/2023]
Abstract
Coeliac disease (CD) is characterized by an intestinal lesion sustained by an abnormal mucosal T-cell response to wheat gliadin. An immunological approach that is able to suppress this immune response is a perspective worth pursuing. Several strategies of antigen administration have been aimed at the downregulation of pathogenic T-cells. In particular, we previously reported a significant suppression of the systemic cell-mediated response toward wheat gliadin in DQ8 transgenic mice receiving nasally a recombinant α-gliadin. To gain further insight about the cellular mechanisms underlying the tolerogenic properties of this molecule, we analysed different preparations of the recombinant α-gliadin, alone or conjugated to the adjuvant cholera toxin (CT), by in vitro challenge with spleen CD4+ T cells from gliadin-sensitized DQ8 tg mice. We found that a partially purified preparation of recombinant α-gliadin (r-gliadin) induced a significantly higher production of IFN-γ than native gliadin as well as HPLC purified r-gliadin. Interestingly, r-gliadin, but not HPLC purified r-gliadin, stimulated the gliadin-specific expression of IL-10 in CD4+ T cells. No significant cytotoxic effect was induced by r-gliadin in MODE-K cells, a murine model of enterocytes. Notably, a conjugate CT-r-gliadin failed in stimulating IFN-γ, whereas IL-10 secretion was still induced in gliadin-specific CD4+ T cells. In conclusion, our results showed that DCs, pulsed with CT-r-gliadin in vitro, could modulate the ongoing Th1-like T cell response toward wheat gliadin. This finding provides new insight into the design of immunomodulatory protocols potentially useful for CD.
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Affiliation(s)
| | | | | | | | - Mauro Rossi
- Institute of Food Sciences, CNR, Avellino, Italy.
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Hooper KM, Yen JH, Kong W, Rahbari KM, Kuo PC, Gamero AM, Ganea D. Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1. THE JOURNAL OF IMMUNOLOGY 2017; 198:1521-1530. [PMID: 28062696 DOI: 10.4049/jimmunol.1601073] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 12/09/2016] [Indexed: 12/20/2022]
Abstract
IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2 We showed previously that PGE2 inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and binding to the p28 IFN-stimulated response element site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1, or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, exchange protein activated by cAMP, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo proinflammatory functions.
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Affiliation(s)
- Kirsten M Hooper
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Jui-Hung Yen
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202
| | - Weimin Kong
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Kate M Rahbari
- Department of Microbiology and Immunology, University of Illinois College of Medicine at Chicago, Chicago, IL 60612; and
| | - Ping-Chang Kuo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Doina Ganea
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
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Tsai HC, Wu R. Mechanisms of Cholera Toxin in the Modulation of TH17 Responses. Crit Rev Immunol 2016; 35:135-52. [PMID: 26351147 DOI: 10.1615/critrevimmunol.2015012295] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Numerous studies have shown that TH17 cells and their signature cytokine IL-17A are critical to host defense against various bacterial and fungal infections. The protective responses mediated by TH17 cells and IL-17A include the recruitment of neutrophils, release of antimicrobial peptides and chemokines, and enhanced tight junction of epithelial cells. Due to the importance of TH17 cells in infections, efforts have been made to develop TH17-based vaccines. The goal of vaccination is to establish a protective immunological memory. Most currently approved vaccines are antibody-based and have limited protection against stereotypically different strains. Studies show that T-cell-based vaccines may overcome this limitation and protect hosts against infection of different strains. Two main strategies are used to develop TH17 vaccines: identification of TH17-specific antigens and TH17-skewing adjuvants. Studies have revealed that cholera toxin (CT) induces a potent Th17 response following vaccination. Antigen vaccination along with CT induces a robust TH17 response, which is sometimes accompanied by TH1 responses. Due to the toxicity of CT, it is hard to apply CT in a clinical setting. Thus, understanding how CT modulates TH17 responses may lead to the development of successful TH17-based vaccines.
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Affiliation(s)
- Hsing-Chuan Tsai
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
| | - Reen Wu
- Center for Comparative Respiratory Biology and Medicine, University of California, USA
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Kim D, Kim YG, Seo SU, Kim DJ, Kamada N, Prescott D, Philpott DJ, Rosenstiel P, Inohara N, Núñez G. Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. Nat Med 2016; 22:524-30. [PMID: 27064448 PMCID: PMC4860092 DOI: 10.1038/nm.4075] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/04/2016] [Indexed: 01/07/2023]
Abstract
Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (TFH) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by Itgax) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with Staphylococcus sciuri, which has high Nod2-stimulatory activity, was sufficient to promote robust CT adjuvant activity, whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.
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Affiliation(s)
- Donghyun Kim
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Yun-Gi Kim
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Sang-Uk Seo
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Dong-Jae Kim
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Dave Prescott
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Dana J. Philpott
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology; University of Kiel, Kiel, Germany
| | - Naohiro Inohara
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gabriel Núñez
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
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15
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Differential Impact of LPG-and PG-Deficient Leishmania major Mutants on the Immune Response of Human Dendritic Cells. PLoS Negl Trop Dis 2015; 9:e0004238. [PMID: 26630499 PMCID: PMC4667916 DOI: 10.1371/journal.pntd.0004238] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 10/25/2015] [Indexed: 11/30/2022] Open
Abstract
Background Leishmania major infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of Leishmania parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction. Methodology/Principal Findings Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating L. major Friedlin V1 mutants defective in LPG alone, (FV1 lpg1-), or generally deficient for all PGs, (FV1 lpg2-). Infection with metacyclic, infective stage, L. major or purified LPG induced high levels of IL12B subunit gene transcripts in hDCs, which was abrogated with FV1 lpg1- infections. In contrast, hDC infections with FV1 lpg2- displayed increased IL12B expression, suggesting other PG-related/LPG2 dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 lpg1-, FV1 lpg2- infections revealed that FV1 lpg1- mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription. Conclusions/Significance These data suggest that L. major LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring Leishmania surface glycoconjugates that result in modulation of host cellular IL12. Leishmaniasis is a group of parasitic diseases caused by intracellular protozoa belonging to the genus Leishmania, pathological manifestations ranging from self-healing cutaneous forms to severe visceral infections that result in death. These clinical outcomes are dictated by the Leishmania species initiating the infection and are influenced by early responses of host immune cells, which ultimately initiate an IL12 mediated immune response in resolving infections. Like the diseases themselves, the magnitude of IL12 induction in hDCs is Leishmania-species and strain specific, where species that elicit visceral disease do not induce IL12, while most cutaneous disease-causing L. major strains induce robust IL12 responses and confer life-long immunity. The molecular mechanisms that mediate the ability of these innate immune cells to discriminate between pathogens remain elusive and have been primarily investigated in murine model systems. Here we identified L. major LPG as a major PAMP that induces IL12 in hDCs. Elucidation of this critical component of human immunity to L. major has ramifications for leishmaniasis vaccine development.
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Cholera toxin adjuvant promotes a balanced Th1/Th2/Th17 response independently of IL-12 and IL-17 by acting on Gsα in CD11b⁺ DCs. Mucosal Immunol 2015; 8:815-27. [PMID: 25425266 DOI: 10.1038/mi.2014.111] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Accepted: 10/06/2014] [Indexed: 02/04/2023]
Abstract
Despite an extensive literature on the mechanism of action of cholera toxin (CT), we still lack critical information about how the toxin acts as an adjuvant and, especially, which dendritic cells (DCs) are the target cells. Although a T helper type 2 (Th2)-skewing effect of CT is most commonly reported, effective priming of Th17 cells as well as suppression of Th1 responses are well documented. However, the ability of CT to block interferon regulatory factor 8 (IRF8) function and interleukin (IL)-12 production in DCs, which blocks CD8α DC and Th1 cell development, is inconsistent with priming of Th1 and CD8 T cells in many other reports. This prompted us to investigate the adjuvant effect of CT in wild-type, IL-12p40-/-, Batf3-/-, and IL-17A-/- mice and in mice that selectively lack the Gsα target protein for CT adenosine diphosphate (ADP)-ribosylation in DCs. We found that CT promoted Th1 priming independently of IL-12, and whereas Th2 and also Th17 responses were augmented, the gut IgA responses did not require IL-17A. Adjuvanticity was intact in Batf3-/- mice, lacking CD8α(+) DCs, but completely lost in mice with Gsα-deficient CD11c cells. Thus, our data demonstrate that the adjuvant effect requires Gsα expression in CD11b(+) DCs, and that priming of mucosal IgA and CD4 T cells appears unbiased and is independent of IL-12 and IL-17A.
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Cerny O, Kamanova J, Masin J, Bibova I, Skopova K, Sebo P. Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase. THE JOURNAL OF IMMUNOLOGY 2015; 194:4901-13. [PMID: 25876760 DOI: 10.4049/jimmunol.1402941] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/10/2015] [Indexed: 12/23/2022]
Abstract
The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in the virulence of Bordetella pertussis. CyaA penetrates complement receptor 3-expressing phagocytes and catalyzes uncontrolled conversion of cytosolic ATP to the key second messenger molecule cAMP. This paralyzes the capacity of neutrophils and macrophages to kill bacteria by complement-dependent oxidative burst and opsonophagocytic mechanisms. We show that cAMP signaling through the protein kinase A (PKA) pathway activates Src homology domain 2 containing protein tyrosine phosphatase (SHP) 1 and suppresses production of bactericidal NO in macrophage cells. Selective activation of PKA by the cell-permeable analog N(6)-benzoyladenosine-3',5'-cyclic monophosphate interfered with LPS-induced inducible NO synthase (iNOS) expression in RAW264.7 macrophages, whereas inhibition of PKA by H-89 largely restored the production of iNOS in CyaA-treated murine macrophages. CyaA/cAMP signaling induced SHP phosphatase-dependent dephosphorylation of the c-Fos subunit of the transcription factor AP-1 and thereby inhibited TLR4-triggered induction of iNOS gene expression. Selective small interfering RNA knockdown of SHP-1, but not of the SHP-2 phosphatase, rescued production of TLR-inducible NO in toxin-treated cells. Finally, inhibition of SHP phosphatase activity by NSC87877 abrogated B. pertussis survival inside murine macrophages. These results reveal that an as yet unknown cAMP-activated signaling pathway controls SHP-1 phosphatase activity and may regulate numerous receptor signaling pathways in leukocytes. Hijacking of SHP-1 by CyaA action then enables B. pertussis to evade NO-mediated killing in sentinel cells of innate immunity.
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Affiliation(s)
- Ondrej Cerny
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the ASCR, v.v.i., Czech Academy of Sciences, 142 20, Prague 4, Czech Republic
| | - Jana Kamanova
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the ASCR, v.v.i., Czech Academy of Sciences, 142 20, Prague 4, Czech Republic
| | - Jiri Masin
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the ASCR, v.v.i., Czech Academy of Sciences, 142 20, Prague 4, Czech Republic
| | - Ilona Bibova
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the ASCR, v.v.i., Czech Academy of Sciences, 142 20, Prague 4, Czech Republic
| | - Karolina Skopova
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the ASCR, v.v.i., Czech Academy of Sciences, 142 20, Prague 4, Czech Republic
| | - Peter Sebo
- Laboratory of Molecular Biology of Bacterial Pathogens, Institute of Microbiology of the ASCR, v.v.i., Czech Academy of Sciences, 142 20, Prague 4, Czech Republic
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18
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19
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Anderl F, Gerhard M. Helicobacter pylori vaccination: Is there a path to protection? World J Gastroenterol 2014; 20:11939-11949. [PMID: 25232229 PMCID: PMC4161780 DOI: 10.3748/wjg.v20.i34.11939] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 03/31/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a pathogenic, extracellular bacterium that colonizes the stomach in approximately 50% of the world population. It strongly interacts with the gastric epithelium and mostly causes asymptomatic gastritis. The colonization of H. pylori leads to ulcer development in around 20% of infected patients and may progress to gastric cancer or mucosa-associated lymphoid tissue lymphoma in 1%. Thus, H. pylori is the major cause of gastric cancer worldwide. It has been classified as a class I carcinogen by the World Health Organization. Since its discovery in the early eighties by Warren and Marshall, research has been focused on the investigation of H. pylori biology, host-pathogen interaction, prevention and treatment. Although H. pylori induces a strong humoral and local cellular immune response, the pathogen is not cleared and establishes a chronic infection after encounters in childhood. The ability to colonize the stomach is mediated by several virulence factors that change the host environment, promote adhesion to the epithelium, influence the gastric inflammation and induce immune evasion. H. pylori can be eradicated by antibiotic treatment in combination with a proton-pump inhibitor, but efficacy is decreasing. Current therapies are expensive, have side effects and contribute to increasing antibiotic resistance, underlining the need for novel therapeutics.
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20
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Sciaraffia E, Riccomi A, Lindstedt R, Gesa V, Cirelli E, Patrizio M, De Magistris MT, Vendetti S. Human monocytes respond to extracellular cAMP through A2A and A2B adenosine receptors. J Leukoc Biol 2014; 96:113-22. [PMID: 24652540 DOI: 10.1189/jlb.3a0513-302rr] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
In this study, we test the hypothesis that cAMP, acting as an extracellular mediator, affects the physiology and function of human myeloid cells. The cAMP is a second messenger recognized as a universal regulator of several cellular functions in different organisms. Many studies have shown that extracellular cAMP exerts regulatory functions, acting as first mediator in multiple tissues. However, the impact of extracellular cAMP on cells of the immune system has not been fully investigated. We found that human monocytes exposed to extracellular cAMP exhibit higher expression of CD14 and lower amount of MHC class I and class II molecules. When cAMP-treated monocytes are exposed to proinflammatory stimuli, they exhibit an increased production of IL-6 and IL-10 and a lower amount of TNF-α and IL-12 compared with control cells, resembling the features of the alternative-activated macrophages or M2 macrophages. In addition, we show that extracellular cAMP affects monocyte differentiation into DCs, promoting the induction of cells displaying an activated, macrophage-like phenotype with reduced capacity of polarized, naive CD4(+) T cells into IFN-γ-producing lymphocytes compared with control cells. The effects of extracellular cAMP on monocytes are mediated by CD73 ecto-5'-nucleotidase and A2A and A2B adenosine receptors, as selective antagonists could reverse its effects. Of note, the expression of CD73 molecules has been found on the membrane of a small population of CD14(+)CD16(+) monocytes. These findings suggest that an extracellular cAMP-adenosine pathway is active in cells of the immune systems.
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Affiliation(s)
- Ester Sciaraffia
- Department of Infectious, Parasitic and Immune-Mediated Diseases, and
| | - Antonella Riccomi
- Department of Infectious, Parasitic and Immune-Mediated Diseases, and
| | - Ragnar Lindstedt
- Department of Infectious, Parasitic and Immune-Mediated Diseases, and
| | - Valentina Gesa
- Department of Infectious, Parasitic and Immune-Mediated Diseases, and
| | - Elisa Cirelli
- Department of Infectious, Parasitic and Immune-Mediated Diseases, and Animal Breeding Department, University of Rome "Tor Vergata", Rome, Italy
| | - Mario Patrizio
- Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy; and
| | | | - Silvia Vendetti
- Department of Infectious, Parasitic and Immune-Mediated Diseases, and
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21
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Griffiths KL, Stylianou E, Poyntz HC, Betts GJ, Fletcher HA, McShane H. Cholera toxin enhances vaccine-induced protection against Mycobacterium tuberculosis challenge in mice. PLoS One 2013; 8:e78312. [PMID: 24194918 PMCID: PMC3806838 DOI: 10.1371/journal.pone.0078312] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 09/13/2013] [Indexed: 12/20/2022] Open
Abstract
Interleukin (IL)-17 is emerging as an important cytokine in vaccine-induced protection against tuberculosis disease in animal models. Here we show that compared to parenteral delivery, BCG delivered mucosally enhances cytokine production, including interferon gamma and IL-17, in the lungs. Furthermore, we find that cholera toxin, delivered mucosally along with BCG, further enhances IL-17 production by CD4(+) T cells over mucosal BCG alone both in the lungs and systemically. This boosting effect of CT is also observed using a vaccine regimen of BCG followed by the candidate vaccine MVA85A. Using a murine Mycobacterium tuberculosis (M.tb) aerosol challenge model, we demonstrate the ability of cholera toxin delivered at the time of a priming BCG vaccination to improve protection against tuberculosis disease in a manner at least partially dependent on the observed increase in IL-17. This observed increase in IL-17 in the lungs has no adverse effect on lung pathology following M.tb challenge, indicating that IL-17 can safely be boosted in murine lungs in a vaccine/M.tb challenge setting.
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Affiliation(s)
| | - Elena Stylianou
- Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Hazel C. Poyntz
- Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Gareth J. Betts
- Jenner Institute, University of Oxford, Oxford, United Kingdom
| | | | - Helen McShane
- Jenner Institute, University of Oxford, Oxford, United Kingdom
- * E-mail:
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22
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Raetz M, Kibardin A, Sturge CR, Pifer R, Li H, Burstein E, Ozato K, Larin S, Yarovinsky F. Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin. THE JOURNAL OF IMMUNOLOGY 2013; 191:4818-27. [PMID: 24078692 DOI: 10.4049/jimmunol.1301301] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-κB, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii.
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Affiliation(s)
- Megan Raetz
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg. Blood 2013; 122:2185-94. [DOI: 10.1182/blood-2012-09-456988] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Key Points
ONTAK blocks DC maturation by coreceptor downmodulation and inhibition of Stat3 phosphorylation to induce a tolerogenic phenotype. ONTAK kills activated CD4 T cells but stimulates antiapoptosis in resting Treg by engagement and stimulation through CD25.
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24
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Li SW, He Y, Zheng ZH, Liu DW, Liu ZS. Single-nucleotide polymorphisms ofIRF8gene are associated with systemic lupus erythematosus in Chinese Han population. Int J Immunogenet 2013; 41:112-8. [PMID: 24034601 DOI: 10.1111/iji.12087] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 07/31/2013] [Accepted: 08/10/2013] [Indexed: 01/16/2023]
Affiliation(s)
- S.-W. Li
- Department of Nephrology; The First Affiliated Hospital of Zhengzhou University; Zhengzhou China
| | - Y. He
- Department of Cell Biology and Medical Genetics; Basic Medical College of Zhengzhou University; Zhengzhou China
| | - Z.-H. Zheng
- Department of Nephrology; The First Affiliated Hospital of Zhengzhou University; Zhengzhou China
| | - D.-W. Liu
- Department of Nephrology; The First Affiliated Hospital of Zhengzhou University; Zhengzhou China
| | - Z.-S. Liu
- Department of Nephrology; The First Affiliated Hospital of Zhengzhou University; Zhengzhou China
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25
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Je JH, Kim DY, Roh HJ, Pak C, Kim DH, Byamba D, Jee H, Kim TG, Park JM, Lee SK, Lee MG. The Antioxidative Effect of Heat-Shock Protein 70 in Dendritic Cells. Scand J Immunol 2013; 78:238-47. [DOI: 10.1111/sji.12078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 04/28/2013] [Indexed: 12/29/2022]
Affiliation(s)
- J. H. Je
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - D. Y. Kim
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - H. J. Roh
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - C. Pak
- Medical Mission Center; Yonsei University Health System; Seoul Korea
| | - D. H. Kim
- Department of Dermatology; CHA University College of Medicine; Seongnam Korea
| | - D. Byamba
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - H. Jee
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - T.-G. Kim
- Department of Environmental Medical Biology; Institute of Tropical Medicine; Yonsei University College of Medicine; Seoul Korea
| | - J. M. Park
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - S.-K. Lee
- Department of Biotechnology; College of Life Science and Biotechnology; National Creative Research Initiatives Center For Inflammatory Response Modulation; Yonsei University; Seoul Korea
| | - M.-G. Lee
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
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Yokoyama U, Iwatsubo K, Umemura M, Fujita T, Ishikawa Y. The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev 2013; 65:1010-52. [PMID: 23776144 DOI: 10.1124/pr.112.007195] [Citation(s) in RCA: 204] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The EP4 prostanoid receptor is one of four receptor subtypes for prostaglandin E2. It belongs to the family of G protein-coupled receptors. It was originally identified, similar to the EP2 receptor as a G(s)α-coupled, adenylyl cyclase-stimulating receptor. EP4 signaling plays a variety of roles through cAMP effectors, i.e., protein kinase A and exchange protein activated by cAMP. However, emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that EP4, unlike EP2, can also be coupled to G(i)α, phosphatidylinositol 3-kinase, β-arrestin, or β-catenin. These signaling pathways constitute unique roles for the EP4 receptor. EP4 is widely distributed in the body and thus plays various physiologic and pathophysiologic roles. In particular, EP4 signaling is closely related to carcinogenesis, cardiac hypertrophy, vasodilation, vascular remodeling, bone remodeling, gastrointestinal homeostasis, renal function, and female reproductive function. In addition to the classic anti-inflammatory action of EP4 on mononuclear cells and T cells, recent evidence has shown that EP4 signaling contributes to proinflammatory action as well. The aim of this review is to present current findings on the biologic functions of the EP4 receptor. In particular, we will discuss its diversity from the standpoint of EP4-mediated signaling.
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Affiliation(s)
- Utako Yokoyama
- Cardiovascular Research Institute, Yokohama City University, Yokohama, Kanagawa, Japan
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Ireland R, Wang R, Alinger JB, Small P, Bosio CM. Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8. THE JOURNAL OF IMMUNOLOGY 2013; 191:1276-86. [PMID: 23817430 DOI: 10.4049/jimmunol.1300867] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity constitute a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. In this article, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated live vaccine strain, inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα-independent inhibition of NF-κBp65 activation and selective inhibition of activation of IFN regulatory factors. Interference with NF-κBp65 and IFN regulatory factors is also observed following infection with viable SchuS4. Together these data provide novel insight into how highly virulent bacteria selectively modulate the host to interfere with innate immune responses required for survival of infection.
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Affiliation(s)
- Robin Ireland
- Immunity to Pulmonary Pathogens Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
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Promotion of colonization and virulence by cholera toxin is dependent on neutrophils. Infect Immun 2013; 81:3338-45. [PMID: 23798539 DOI: 10.1128/iai.00422-13] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The innate immune response to Vibrio cholerae infection is poorly understood, but this knowledge is critical for the design of safe, effective vaccines. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host immunity, as well as the effect of cholera toxin and other secreted factors on this response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to similar survival rates of mice infected with low or moderate doses of toxigenic V. cholerae El Tor O1. At a high dose, neutropenic mice showed increased rates of survival compared to neutrophil-replete animals. Expression of cholera toxin was found to be protective to the neutropenic host, and this phenotype can be replicated by the administration of purified toxin. Neutrophils do not effectively clear colonizing bacteria from the small intestine, nor do they alter induction of early immune-modulating signals. In both neutropenic and neutrophil-replete animals, the local response to infection is characterized by expression of interleukin 6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha (MIP-2). Overall, these data indicate that the innate immune response to toxigenic V. cholerae infection differs dramatically from the host response to nontoxigenic infection or vaccination, where neutrophils are protective to the host. In the absence of neutrophils, cholera toxin induces immunomodulatory effects that increase host survival. In cholera toxin-producing strains, similar to nontoxigenic infection, accessory toxins are critical to virulence, indicating that cholera toxin and the other secreted toxins modulate the host response by different mechanisms, with both contributing to bacterial persistence and virulence.
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Schönheit J, Kuhl C, Gebhardt M, Klett F, Riemke P, Scheller M, Huang G, Naumann R, Leutz A, Stocking C, Priller J, Andrade-Navarro M, Rosenbauer F. PU.1 Level-Directed Chromatin Structure Remodeling at the Irf8 Gene Drives Dendritic Cell Commitment. Cell Rep 2013; 3:1617-28. [DOI: 10.1016/j.celrep.2013.04.007] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 11/23/2012] [Accepted: 04/08/2013] [Indexed: 01/22/2023] Open
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Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatol Ther (Heidelb) 2013; 3:1-15. [PMID: 23888251 PMCID: PMC3680635 DOI: 10.1007/s13555-013-0023-0] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Indexed: 01/10/2023] Open
Abstract
Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed.
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Cho YC, Lee SH, Lee M, Kim HJ, Oak MH, Lee IS, Kang BY. Enhanced IL-12p40 production in LPS-stimulated macrophages by inhibiting JNK activation by artemisinin. Arch Pharm Res 2012; 35:1961-8. [PMID: 23212638 DOI: 10.1007/s12272-012-1113-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2012] [Revised: 06/04/2012] [Accepted: 06/13/2012] [Indexed: 01/19/2023]
Abstract
Artemisinin can be isolated from Artemisia annua L. In addition to its well-known anti-malarial activity, artemisinin has antitumor and anti-microbial effects. In this study, we investigated the effect of artemisinin on the production of IL-12p40, which is important in the generation of T helper 1 responses. Artemisinin significantly induced IL-12p40 production in LPS-stimulated RAW264.7 macrophage cells. To elucidate the signaling molecules regulated by artemisinin in induced IL-12p40 production, the DNA-binding activity of several transcription factors and activation of mitogen-activated protein kinase (MAPK)s were investigated. The band intensities of NF-κB, AP-1, and SP1, and the activation of p38 MAPK and ERK were not changed by artemisinin. However, the induced phosphorylation of JNK was significantly decreased by artemisinin, and inhibition of the JNK signaling pathway further increased IL-12p40 production in LPS-stimulated RAW264.7 macrophage cells. Taken together, these data suggest that artemisinin induces the production of IL-12p40 in LPS-stimulated macrophage cells by inhibiting JNK activity.
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Affiliation(s)
- Young-Chang Cho
- College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea
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32
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Hajishengallis G, Connell TD. Type II heat-labile enterotoxins: structure, function, and immunomodulatory properties. Vet Immunol Immunopathol 2012; 152:68-77. [PMID: 23137790 DOI: 10.1016/j.vetimm.2012.09.034] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The heat-labile enterotoxins (HLTs) of Escherichia coli and Vibrio cholerae are classified into two major types on the basis of genetic, biochemical, and immunological properties. Type I and Type II HLT have been intensively studied for their exceptionally strong adjuvant activities. Despite general structural similarities, these molecules, in intact or derivative (non-toxic) forms, display notable differences in their mode of immunomodulatory action. The molecular basis of these differences has remained largely uncharacterized until recently. This review focuses on the Type II HLTs and their immunomodulatory properties which depend largely on interactions with unique gangliosides and Toll-like receptors that are not utilized by the Type I HLTs.
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Affiliation(s)
- George Hajishengallis
- University of Pennsylvania School of Dental Medicine, Department of Microbiology, Philadelphia, PA 19104, USA.
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Okada Y, Oh-oka K, Nakamura Y, Ishimaru K, Matsuoka S, Okumura K, Ogawa H, Hisamoto M, Okuda T, Nakao A. Dietary resveratrol prevents the development of food allergy in mice. PLoS One 2012; 7:e44338. [PMID: 22962611 PMCID: PMC3433457 DOI: 10.1371/journal.pone.0044338] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Accepted: 07/24/2012] [Indexed: 11/29/2022] Open
Abstract
Background Resveratrol is a bioactive polyphenol enriched in red wine that exhibits many beneficial health effects via multiple mechanisms. However, it is unclear whether resveratrol is beneficial for the prevention of food allergy. This study investigated whether resveratrol inhibited the development of food allergy by using a mouse model of the disease. Methodology/Principal Findings Mice fed standard diet or standard diet plus resveratrol were sensitized by intragastric administration of ovalbumin (OVA) and mucosal adjuvant cholera toxin (CT). Several manifestations of food allergy were then compared between the mice. The effects of resveratrol on T cells or dendritic cells were also examined by using splenocytes from OVA-specific T cell-receptor (TCR) transgenic DO11.10 mice or mouse bone marrow-derived dendritic cells (BMDCs) in vitro. We found that mice fed resveratrol showed reduced OVA-specific serum IgE production, anaphylactic reaction, and OVA-induced IL-13 and IFN-ã production from the mesenteric lymph nodes (MLNs) and spleens in comparison to the control mice, following oral sensitization with OVA plus CT. In addition, resveratrol inhibited OVA plus CT-induced IL-4, IL-13, and IFN-ã production in splenocytes from DO11.10 mice associated with inhibition of GATA-3 and T-bet expression. Furthermore, resveratrol suppressed the OVA plus CT-induced CD25 expression and IL-2 production in DO11.10 mice-splenocytes in association with decreases in CD80 and CD86 expression levels. Finally, resveratrol suppressed CT-induced cAMP elevation in association with decreases in CD80 and CD86 expression levels in BMDCs. Conclusions/Significance Ingestion of resveratrol prevented the development of a food allergy model in mice. Given the in vitro findings, resveratrol might do so by inhibiting DC maturation and subsequent early T cell activation and differentiation via downregulation of CT-induced cAMP activation in mice. These results suggest that resveratrol may have potential for prophylaxis against food allergy.
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Affiliation(s)
- Yui Okada
- Department of Immunology, University of Yamanashi Faculty of Medicine Chuo, Yamanashi, Japan
- The Institute of Enology and Viticulture, University of Yamanashi, Koufu, Yamanashi, Japan
| | - Kyoko Oh-oka
- Department of Immunology, University of Yamanashi Faculty of Medicine Chuo, Yamanashi, Japan
| | - Yuki Nakamura
- Department of Immunology, University of Yamanashi Faculty of Medicine Chuo, Yamanashi, Japan
| | - Kayoko Ishimaru
- Department of Immunology, University of Yamanashi Faculty of Medicine Chuo, Yamanashi, Japan
| | - Shuji Matsuoka
- Deparment of Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Ko Okumura
- Atopy Research Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Hideoki Ogawa
- Atopy Research Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Masashi Hisamoto
- The Institute of Enology and Viticulture, University of Yamanashi, Koufu, Yamanashi, Japan
| | - Tohru Okuda
- The Institute of Enology and Viticulture, University of Yamanashi, Koufu, Yamanashi, Japan
| | - Atsuhito Nakao
- Department of Immunology, University of Yamanashi Faculty of Medicine Chuo, Yamanashi, Japan
- Atopy Research Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
- * E-mail:
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Ruiter B, Shreffler WG. Innate immunostimulatory properties of allergens and their relevance to food allergy. Semin Immunopathol 2012; 34:617-32. [PMID: 22886110 DOI: 10.1007/s00281-012-0334-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 07/10/2012] [Indexed: 12/12/2022]
Abstract
Food allergy is an increasingly prevalent disease of immune dysregulation directed to a small subset of proteins. Shared structural and functional features of allergens, such as glycosylation, lipid-binding and protease activity may provide insight into the mechanisms involved in the induction of primary Th2 immune responses. We review the literature of innate Th2-type immune activation as a context for better understanding the properties of allergens that contribute to the induction of Th2-biased immune responses in at least a subset of individuals. Th2-priming signals have been largely identified in the context of parasite immunity and wound healing. Some of the features of parasite antigens and the innate immune responses to them are now understood to play a role in allergic inflammation as well. These include both exogenous and endogenous activators of innate immunity and subsequent release of key cytokine mediators such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33. Moreover, numerous innate immune cells including epithelium, dendritic cells, basophils, innate lymphoid cells and others all interact to shape the adaptive Th2 immune response. Progress toward understanding Th2-inducing innate immune signals more completely may lead to novel strategies for primary prevention and therapy of respiratory and food allergies.
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Affiliation(s)
- Bert Ruiter
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
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35
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Neutrophils are essential for containment of Vibrio cholerae to the intestine during the proinflammatory phase of infection. Infect Immun 2012; 80:2905-13. [PMID: 22615254 DOI: 10.1128/iai.00356-12] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cholera is classically considered a noninflammatory diarrheal disease, in comparison to invasive enteric organisms, although there is a low-level proinflammatory response during early infection with Vibrio cholerae and a strong proinflammatory reaction to live attenuated vaccine strains. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host defense to infection. Nontoxigenic El Tor O1 V. cholerae infection is characterized by the upregulation of interleukin-6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha in the intestine, indicating an acute innate immune response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to decreased survival of mice. The role of neutrophils in protection of the host is to limit the infection to the intestine and control bacterial spread to extraintestinal organs. In the absence of neutrophils, the infection spread to the spleen and led to increased systemic levels of IL-1β and tumor necrosis factor alpha, suggesting the decreased survival in neutropenic mice is due to systemic shock. Neutrophils were found not to contribute to either clearance of colonizing bacteria or to alter the local immune response. However, when genes for secreted accessory toxins were deleted, the colonizing bacteria were cleared from the intestine, and this clearance is dependent upon neutrophils. Thus, the requirement for accessory toxins in virulence is negated in neutropenic mice, which is consistent with a role of accessory toxins in the evasion of innate immune cells in the intestine. Overall, these data support that neutrophils impact disease progression and suggest that neutrophil effectiveness can be manipulated through the deletion of accessory toxins.
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36
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Mauricio Rueda C, Andrea Velilla P, Rojas M, Teresa Rugeles M. AMPc: una molécula clave en los eventos de regulación inmune y en el control de la replicación del VIH. INFECTIO 2012. [DOI: 10.1016/s0123-9392(12)70058-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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37
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Mitchell L, Brzoza-Lewis K, Henry C, Grayson J, Westcott M, Hiltbold E. Distinct responses of splenic dendritic cell subsets to infection with Listeria monocytogenes: maturation phenotype, level of infection, and T cell priming capacity ex vivo. Cell Immunol 2011; 268:79-86. [PMID: 21457950 PMCID: PMC3078036 DOI: 10.1016/j.cellimm.2011.03.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Revised: 02/08/2011] [Accepted: 03/04/2011] [Indexed: 12/22/2022]
Abstract
To determine the relative contributions of DC subsets in the development of protective immunity to Listeria monocytogenes we examined the relationship between maturation, bacterial burden, and T cell priming capacity of four well characterized subsets of splenic DC following infection with Lm. CD8α(+), CD4(+), and CD8α(-)CD4(-) DC and the B220(+) plasmacytoid DC (pDC) were compared for abundance and costimulatory molecule expression at 24, 48, and 72h post i.v. infection. We further determined the bacterial burden associated with each DC subset and their relative capacities to prime CD8(+) T cells at 24hpi. The CD8α(+) DC displayed the highest level of maturation, association with live bacteria, and T cell activation potential. Second, the CD4(+) DC were also mature, yet were associated with fewer bacteria, and stimulated T cell proliferation, but not IFN-γ production. The CD8α(-)CD4(-) DC showed a modest maturation response and were associated with a high number of bacteria, but failed to induce T cell proliferation ex vivo. pDC displayed a strong maturation response, but were not associated with detectable bacteria and also failed to stimulate T cell activation. Finally, we measured the cytokine responses in these subsets and determined that IL-12 was produced predominantly by the CD8(+) DC, correlating with the ability of this subset DC to induce IFN-γ production in T cells. We conclude that Listeria-specific CD8(+) T cell activation in the spleen is most effectively achieved by infection-induced maturation of the CD8α(+) DC subset.
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Affiliation(s)
- L.M. Mitchell
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - K.L Brzoza-Lewis
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - C.J. Henry
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - J.M. Grayson
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - M.M. Westcott
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - E.M Hiltbold
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
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38
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Dittmar T, Zänker KS. Horizontal gene transfers with or without cell fusions in all categories of the living matter. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 714:5-89. [PMID: 21506007 PMCID: PMC7120942 DOI: 10.1007/978-94-007-0782-5_2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This article reviews the history of widespread exchanges of genetic segments initiated over 3 billion years ago, to be part of their life style, by sphero-protoplastic cells, the ancestors of archaea, prokaryota, and eukaryota. These primordial cells shared a hostile anaerobic and overheated environment and competed for survival. "Coexist with, or subdue and conquer, expropriate its most useful possessions, or symbiose with it, your competitor" remain cellular life's basic rules. This author emphasizes the role of viruses, both in mediating cell fusions, such as the formation of the first eukaryotic cell(s) from a united crenarchaeon and prokaryota, and the transfer of host cell genes integrated into viral (phages) genomes. After rising above the Darwinian threshold, rigid rules of speciation and vertical inheritance in the three domains of life were established, but horizontal gene transfers with or without cell fusions were never abolished. The author proves with extensive, yet highly selective documentation, that not only unicellular microorganisms, but the most complex multicellular entities of the highest ranks resort to, and practice, cell fusions, and donate and accept horizontally (laterally) transferred genes. Cell fusions and horizontally exchanged genetic materials remain the fundamental attributes and inherent characteristics of the living matter, whether occurring accidentally or sought after intentionally. These events occur to cells stagnating for some 3 milliard years at a lower yet amazingly sophisticated level of evolution, and to cells achieving the highest degree of differentiation, and thus functioning in dependence on the support of a most advanced multicellular host, like those of the human brain. No living cell is completely exempt from gene drains or gene insertions.
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Affiliation(s)
- Thomas Dittmar
- Inst. Immunologie, Universität Witten/Herdecke, Stockumer Str. 10, Witten, 58448 Germany
| | - Kurt S. Zänker
- Institute of Immunologie, University of Witten/Herdecke, Stockumer Str. 10, Witten, 58448 Germany
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Cholera toxin impairs the differentiation of monocytes into dendritic cells, inducing professional antigen-presenting myeloid cells. Infect Immun 2010; 79:1300-10. [PMID: 21149590 DOI: 10.1128/iai.01181-10] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Cholera toxin (CT) is a potent adjuvant for mucosal vaccination; however, its mechanism of action has not been clarified completely. It is well established that peripheral monocytes differentiate into dendritic cells (DCs) both in vitro and in vivo and that monocytes are the in vivo precursors of mucosal CD103(-) proinflammatory DCs. In this study, we asked whether CT had any effects on the differentiation of monocytes into DCs. We found that CT-treated monocytes, in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4), failed to differentiate into classical DCs (CD14(low) CD1a(high)) and acquired a macrophage-like phenotype (CD14(high) CD1a(low)). Cells differentiated in the presence of CT expressed high levels of major histocompatibility complex class I (MHC-I) and MHC-II and CD80 and CD86 costimulatory molecules and produced larger amounts of IL-1β, IL-6, and IL-10 but smaller amounts of tumor necrosis factor alpha (TNF-α) and IL-12 than did monocytes differentiated into DCs in the absence of CT. The enzymatic activity of CT was found to be important for the skewing of monocytes toward a macrophage-like phenotype (Ma-DCs) with enhanced antigen-presenting functions. Indeed, treatment of monocytes with scalar doses of forskolin (FSK), an activator of adenylate cyclase, induced them to differentiate in a dose-dependent manner into a population with phenotype and functions similar to those found after CT treatment. Monocytes differentiated in the presence of CT induced the differentiation of naïve T lymphocytes toward a Th2 phenotype. Interestingly, we found that CT interferes with the differentiation of monocytes into DCs in vivo and promotes the induction of activated antigen-presenting cells (APCs) following systemic immunization.
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40
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Mucosal adjuvants and long-term memory development with special focus on CTA1-DD and other ADP-ribosylating toxins. Mucosal Immunol 2010; 3:556-66. [PMID: 20844480 DOI: 10.1038/mi.2010.54] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The ultimate goal for vaccination is to stimulate protective immunological memory. Protection against infectious diseases not only relies on the magnitude of the humoral immune response, but more importantly on the quality and longevity of it. Adjuvants are critical components of most non-living vaccines. Although little attention has been given to qualitative aspects of the choice of vaccine adjuvant, emerging data demonstrate that this function may be central to vaccine efficacy. In this review we describe efforts to understand more about how adjuvants influence qualitative aspects of memory development. We describe recent advances in understanding how vaccines induce long-lived plasma and memory B cells, and focus our presentation on the germinal center reaction. As mucosal vaccination requires powerful adjuvants, we have devoted much attention to the adenosine diphosphate (ADP)-ribosylating cholera toxin and the CTA1-DD adjuvants as examples of how mucosal adjuvants can influence induction of long-term memory.
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41
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Nurkkala M, Wassén L, Nordström I, Gustavsson I, Slavica L, Josefsson A, Eriksson K. Conjugation of HPV16 E7 to cholera toxin enhances the HPV-specific T-cell recall responses to pulsed dendritic cells in vitro in women with cervical dysplasia. Vaccine 2010; 28:5828-36. [PMID: 20600477 DOI: 10.1016/j.vaccine.2010.06.068] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2009] [Revised: 05/31/2010] [Accepted: 06/22/2010] [Indexed: 11/30/2022]
Abstract
We have evaluated whether cholera toxin (CT) as a carrier/adjuvant can enhance human T-cell responses to a viral oncoprotein in vitro using dendritic cells (DCs) as antigen-presenting cells. Monocyte-derived DCs obtained from women with cervical dysplasia were pulsed with the HPV16 oncoprotein E7, either alone or conjugated to CT, and tested for their ability to induce antigen-specific activation of autologous T cells in vitro. CT-conjugation of E7 significantly improved the capacity of pulsed DCs to activate antigen-specific CD4+ T-cell proliferation and IFN-gamma secretion. The CT-E7-pulsed DCs also produced significantly more of the Th1-inducing cytokine IL-12 compared to DCs pulsed with E7 or CT alone. Furthermore, DCs pulsed with CT-conjugated HPV16 E7 caused a response in T cells from women with advanced disease (CIN III) as well as in T cells from women that were currently not infected with HPV16. These data show the potential of using CT-conjugated viral oncoproteins for DC-induced T-cell activation in humans.
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Affiliation(s)
- Merja Nurkkala
- Department of Rheumatology & Inflammation Research, University of Gothenburg, Göteborg, Sweden.
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42
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Liang S, Hajishengallis G. Heat-Labile Enterotoxins as Adjuvants or Anti-Inflammatory Agents. Immunol Invest 2010; 39:449-67. [DOI: 10.3109/08820130903563998] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Shuang Liang
- University of Louisville School of Dentistry, Oral Health and Systemic Disease, Louisville, KY, USA
| | - George Hajishengallis
- University of Louisville School of Dentistry, Oral Health and Systemic Disease, Louisville, KY, USA
- University of Louisville School of Medicine, Department of Microbiology and Immunology, Louisville, KY, USA
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43
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Toxins-useful biochemical tools for leukocyte research. Toxins (Basel) 2010; 2:428-52. [PMID: 22069594 PMCID: PMC3153219 DOI: 10.3390/toxins2040428] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Accepted: 03/24/2010] [Indexed: 12/28/2022] Open
Abstract
Leukocytes are a heterogeneous group of cells that display differences in anatomic localization, cell surface phenotype, and function. The different subtypes include e.g., granulocytes, monocytes, dendritic cells, T cells, B cells and NK cells. These different cell types represent the cellular component of innate and adaptive immunity. Using certain toxins such as pertussis toxin, cholera toxin or clostridium difficile toxin, the regulatory functions of Gαi, Gαs and small GTPases of the Rho family in leukocytes have been reported. A summary of these reports is discussed in this review.
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44
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Li Y, Lu HM, Li G, Yan GM. Glycogen synthase kinase-3beta regulates astrocytic differentiation of U87-MG human glioblastoma cells. Acta Pharmacol Sin 2010; 31:355-60. [PMID: 20154711 DOI: 10.1038/aps.2010.10] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
AIM To evaluate the role of glycogen synthase kinase-3beta (GSK-3beta) in the induced differentiation of human glioblastoma cells. METHODS Cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation assay. The protein level of p-GSK-3beta, GSK-3beta, glial fibrillary acidic protein (GFAP) and proliferating cell nuclear antigen (PCNA) were determined using Western blots. The overexpression of mutant GSK-3beta was analyzed by immunocytochemistry. RESULTS The biotoxin cholera toxin is capable of inducing differentiation of U87-MG human glioblastoma cells, which is characterized by morphological changes to astrocytic phenotype, increase in differentiation marker protein GFAP and decrease in proliferation. GSK-3beta activation is induced during this differentiation. Small interfering RNA against GSK-3beta suppresses the induced-differentiation in U87-MG cells. Conversely, overexpression of a constitutively active form of human GSK-3beta (pcDNA3-GSK-3beta-S9A) mutant leads to differentiation of U87-MG cells. CONCLUSION Our findings suggest that GSK-3beta plays an important role in astrocytic differentiation of human glioblastoma cells and may be a novel therapeutic target in the malignant tumor.
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Lin Y, Slight SR, Khader SA. Th17 cytokines and vaccine-induced immunity. Semin Immunopathol 2010; 32:79-90. [PMID: 20112107 PMCID: PMC2855296 DOI: 10.1007/s00281-009-0191-2] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Accepted: 12/21/2009] [Indexed: 12/15/2022]
Abstract
T helper type 17 (Th17) cells are a distinct lineage of T cells that produce the effector molecules IL-17, IL-17F, IL-21, and IL-22. Although the role of Th17 cells in primary immune responses against infections is well documented, there is growing evidence that the Th17 lineage maybe critical for vaccine-induced memory immune responses against infectious diseases. Here, we summarize recent progress in our understanding of the role of IL-17 in vaccine-induced immunity.
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Affiliation(s)
- Yinyao Lin
- Department of Pediatrics and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
| | - Samantha R. Slight
- Department of Pediatrics and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
| | - Shabaana A. Khader
- Department of Pediatrics and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
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Ring S, Karakhanova S, Johnson T, Enk AH, Mahnke K. Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8(+) T cells. J Allergy Clin Immunol 2010; 125:237-46.e1-7. [PMID: 20109751 DOI: 10.1016/j.jaci.2009.10.025] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Revised: 09/28/2009] [Accepted: 10/06/2009] [Indexed: 11/15/2022]
Abstract
BACKGROUND Regulatory T (Treg) cells suppress the sensitization phase of experimental contact hypersensitivity (CHS) reactions when injected before hapten application. OBJECTIVE Our aim was to analyze the mechanisms by which Treg cells suppress the sensitization phase of CHS reactions. METHODS Treg cells were labeled with different fluorescent dyes and injected into naive mice directly before sensitization with the hapten 2,4,6-trinitro-1-chlorobenzene. Two days after sensitization, the lymphoid organs were analyzed for the presence of Treg cells and engagement of gap junctions with other cells. Dendritic cells (DCs) and effector CD8(+)T cells were isolated from the draining lymph nodes (LNs) of the differently treated groups, analyzed by using FACS for activation markers, and assessed for the T-cell stimulatory capacity of the DCs and the priming of effector T cells. RESULTS Only the LN-homing Treg cells suppressed the sensitization phase in CHS reactions by means of establishing gap junctions with DCs in the dLNs. This gap junctional intercellular communication led to downregulation of T-cell costimulatory molecules on the surface of the DCs, abrogating the priming, activation, and proliferation of hapten-specific CD8(+)T cells. Consequently, the ear-swelling response induced by challenge with the respective hapten was prevented. CONCLUSION Treg cells not only modulate ongoing CD4(+)T cell-mediated immune reactions at tissue sites but also abrogate the de novo induction of CD8(+)T cell-driven immune reactions by interfering with T-cell stimulatory activity of DCs through gap junctional intercellular communication.
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Affiliation(s)
- Sabine Ring
- Department of Dermatology, University Hospital Heidelberg, Vossstrasse 11, 69115 Heidelberg, Germany.
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Abstract
The skin has been investigated as a site for vaccine delivery only since the late 1990s. However, much has been discovered about the cell populations that reside in the skin, their active role in immune responses, and the fate of trans- cutaneously applied antigens. Transcutaneous immunization (TCI) is a safe, effective means of inducing immune responses against a number of pathogens. One of the most notable benefits of TCI is the induction of immune responses in both systemic and mucosal compartments. This chapter focuses on the transport of antigen into and beyond intact skin, the cutaneous sentinel cell populations that play a role in TCI, and the types of mucosal immune responses that have been generated. A number of in vivo studies in murine models have provided information about the broad responses induced by TCI. Cellular and humoral responses and protection against challenge have been noted in the gastrointestinal, reproductive, and respiratory tracts. Clinical trials have demonstrated the benefits of this vaccine delivery route in humans. As with other routes of immunization, the type of vaccine formulation and choice of adjuvant may be critical for achieving appropriate responses and can be tailored to activate specific immune-responsive cells in the skin to increase the efficacy of TCI against mucosal pathogens.
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