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      IL-33 Is Produced by Mast Cells and Regulates IgE-Dependent Inflammation

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      PLoS ONE
      Public Library of Science

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          Abstract

          Background

          IL-33 is a recently characterized IL-1 family cytokine and found to be expressed in inflammatory diseases, including severe asthma and inflammatory bowl disease. Recombinant IL-33 has been shown to enhance Th2-associated immune responses and potently increase mast cell proliferation and cytokine production. While IL-33 is constitutively expressed in endothelial and epithelial cells, where it may function as a transcriptional regulator, cellular sources of IL-33 and its role in inflammation remain unclear.

          Methodology/Principal Findings

          Here, we identify mast cells as IL-33 producing cells. IgE/antigen activation of bone marrow-derived mast cells or a murine mast cell line (MC/9) significantly enhanced IL-33. Conversely, recombinant IL-33 directly activated mast cells to produce several cytokines including IL-4, IL-5 and IL-6 but not IL-33. We show that expression of IL-33 in response to IgE-activation required calcium and that ionomycin was sufficient to induce IL-33. In vivo, peritoneal mast cells expressed IL-33 and IL-33 levels were significantly lower within the skin of mast cell deficient mice, compared to littermate controls. Local activation of mast cells promotes edema, followed by the recruitment of inflammatory cells. We demonstrate using passive cutaneous anaphylaxis, a mast cell-dependent model, that deficiency in ST2 or antibody blockage of ST2 or IL-33 ablated the late phase inflammatory response but that the immediate phase response was unaffected. IL-33 levels in the skin were significantly elevated only during the late phase.

          Conclusions/Significance

          Our findings demonstrate that mast cells produce IL-33 after IgE-mediated activation and that the IL-33/ST2 pathway is critical for the progression of IgE-dependent inflammation.

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          Most cited references38

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          Mast cells in the development of adaptive immune responses.

          Mast cells are so widely recognized as critical effector cells in allergic disorders and other immunoglobulin E-associated acquired immune responses that it can be difficult to think of them in any other context. However, mast cells also can be important as initiators and effectors of innate immunity. In addition, mast cells that are activated during innate immune responses to pathogens, or in other contexts, can secrete products and have cellular functions with the potential to facilitate the development, amplify the magnitude or regulate the kinetics of adaptive immune responses. Thus, mast cells may influence the development, intensity and duration of adaptive immune responses that contribute to host defense, allergy and autoimmunity, rather than simply functioning as effector cells in these settings.
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            Integrated signalling pathways for mast-cell activation.

            Mast-cell activation mediated by the high-affinity receptor for IgE (FcepsilonRI) is considered to be a key event in the allergic inflammatory response. However, in a physiological setting, other receptors, such as KIT, might also markedly influence the release of mediators by mast cells. Recent studies have provided evidence that FcepsilonRI-dependent degranulation is regulated by two complementary signalling pathways, one of which activates phospholipase Cgamma and the other of which activates phosphatidylinositol 3-kinase, using specific transmembrane and cytosolic adaptor molecules. In this Review, we discuss the evidence for these interacting pathways and describe how the capacity of KIT, and other receptors, to influence FcepsilonRI-dependent mast-cell-mediator release might be a function of the relative abilities of these receptors to activate these alternative pathways.
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              Immunomodulatory mast cells: negative, as well as positive, regulators of immunity.

              Mast cells can promote inflammation and other tissue changes in IgE-associated allergic disorders, as well as in certain innate and adaptive immune responses that are thought to be independent of IgE. However, mast cells can also have anti-inflammatory and immunosuppressive functions. Here, we review the evidence that mast cells can have negative, as well as positive, immunomodulatory roles in vivo, and we propose that mast cells can both enhance and later suppress certain features of an immune response.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                3 August 2010
                : 5
                : 8
                : e11944
                Affiliations
                [1]Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
                New York University, United States of America
                Author notes

                Conceived and designed the experiments: PJB. Performed the experiments: CLH CN PJB. Analyzed the data: CLH CN PJB. Wrote the paper: CLH PJB.

                Article
                10-PONE-RA-19495R1
                10.1371/journal.pone.0011944
                2914748
                20689814
                6b76e49a-e6a5-4b40-802b-68fe87712153
                Hsu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 3 June 2010
                : 10 July 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Immunology
                Immunology/Allergy and Hypersensitivity
                Immunology/Immune Response

                Uncategorized
                Uncategorized

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