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

Xu, D. et al. (2008) IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proceedings of the National Academy of Sciences of the United States of America, 105(31), pp. 10913-10918. (doi: 10.1073/pnas.0801898105) (PMID:18667700) (PMCID:PMC2491487)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and McInnes, Professor Iain and Xu, Dr Damo and Fraser, Dr Alasdair and Pitman, Dr Nick and Kurowska-Stolarska, Professor Mariola and Jiang, Dr Hui-Rong
Authors: Xu, D., Jiang, H.-R., Kewin, P., Li, Y., Mu, R., Fraser, A. R., Pitman, N., Kurowska-Stolarska, M., McKenzie, A. N. J., McInnes, I. B., and Liew, F. Y.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN (Online):1091-6490
Published Online:30 July 2008

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
378571The role of a novel cytokine (EB13-IL12p35) in asthmaNick PitmanMedical Research Council (MRC)G84/6704Institute of Infection Immunity and Inflammation
241511Characterisation of genes differentially expressed on subsets of T lymphocytesFoo LiewMedical Research Council (MRC)G9818261Infection Immunity and Inflammation Medicine
486461The role of IL-35 in infection and inflammationFoo LiewMedical Research Council (MRC)G0801198III -IMMUNOLOGY