IL-33 Is Produced by Mast Cells and Regulates IgE-Dependent Inflammation
Open Access
- 3 August 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 5 (8), e11944
- https://doi.org/10.1371/journal.pone.0011944
Abstract
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. 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. 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.Keywords
This publication has 55 references indexed in Scilit:
- Increased Expression of IL-33 in Severe Asthma: Evidence of Expression by Airway Smooth Muscle CellsThe Journal of Immunology, 2009
- The precursor form of IL-1α is an intracrine proinflammatory activator of transcriptionProceedings of the National Academy of Sciences of the United States of America, 2004
- Further Checkpoints in Th1 DevelopmentImmunity, 2002
- Toll-like receptor 4-mediated activation of murine mast cellsJournal of Leukocyte Biology, 2001
- A new mathematical model for relative quantification in real-time RT-PCRNucleic Acids Research, 2001
- A Comparison of Mediators Released or Generated by IFN-γ-Treated Human Mast Cells Following Aggregation of FcγRI or FcεRIThe Journal of Immunology, 2001
- Regulation of human intestinal mast cells by stem cell factor and IL-4Immunological Reviews, 2001
- IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine productionProceedings of the National Academy of Sciences of the United States of America, 2000
- Ligation of IgE receptors causes an anaphylactic response and neutrophil infiltration but does not induce eosinophilic inflammation in miceJournal of Allergy and Clinical Immunology, 2000
- Human Intestinal Mast Cells Are Capable of Producing Different Cytokine Profiles: Role of IgE Receptor Cross-Linking and IL-4The Journal of Immunology, 2000