IL-33 exacerbates antigen-induced arthritis by activating mast cells |
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Authors: | Xu Damo Jiang Hui-Rong Kewin Peter Li Yubin Mu Rong Fraser Alasdair R Pitman Nick Kurowska-Stolarska Mariola McKenzie Andrew N J McInnes Iain B Liew Foo Y |
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Institution: | Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, United Kingdom. d.xu@clinmed.gla.ac.uk |
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Abstract: | IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor α-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFα, and IFNγ), and antibody production. Conversely, treatment of wild-type (WT) but not ST2−/− mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2−/− mice engrafted with mast cells from WT but not from ST2−/− mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA. |
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Keywords: | Rheumatoid arthritis ST2 |
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