Xu, Damo and Jiang, Hui-Rong and Kewin, Peter and Li, Yubin and Mu, Rong and Fraser, Alasdair R and Pitman, Nick and Kurowska-Stolarska, Mariola and McKenzie, Andrew N J and McInnes, Iain B and Liew, Foo Y (2008) IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proceedings of the National Academy of Sciences, 105 (31). pp. 10913-10918.Full text not available in this repository. (Request a copy from the Strathclyde author)
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 alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), 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.
|Keywords:||animals, arthritis, enzyme-linked immunosorbent assay, flow cytometry, humans, interleukins, mast cells, membrane proteins, mice, receptors, synovial membrane, Therapeutics. Pharmacology, General|
|Subjects:||Medicine > Therapeutics. Pharmacology|
|Department:||Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences|
|Depositing user:||Pure Administrator|
|Date Deposited:||24 Aug 2011 12:06|
|Last modified:||03 Feb 2017 03:24|