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IL-33 exacerbates antigen-induced arthritis by activating mast cells

2008; National Academy of Sciences; Volume: 105; Issue: 31 Linguagem: Inglês

10.1073/pnas.0801898105

1091-6490

Damo Xu, Hui‐Rong Jiang, Peter Kewin, Yubin Li, Rong Mu, Alasdair R. Fraser, Nick Pitman, Mariola Kurowska‐Stolarska, Andrew N. J. McKenzie, Iain B. McInnes, Foo Y. Liew,

Autoimmune and Inflammatory Disorders Research

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.