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Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis

Toy, Dean
Smith, Dirk E.
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Published in Arthritis and rheumatism. 2009, vol. 60, no. 3, p. 738-49
Abstract OBJECTIVE: Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis. METHODS: IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling. RESULTS: IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1beta and/or tumor necrosis factor alpha. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-gamma production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment. CONCLUSION: IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.
Keywords AgedAnimalsAntibodies, Anti-Idiotypic/pharmacologyArthritis, Experimental/chemically induced/metabolism/pathologyArthritis, Rheumatoid/metabolism/pathologyCells, CulturedCollagenDisease Models, AnimalFemaleHumansInterferon-gamma/metabolismInterleukin-17/metabolismInterleukins/metabolismMaleMembrane Proteins/antagonists & inhibitors/metabolismMiceMice, Inbred BALB CMice, Inbred DBAMiddle AgedRANK Ligand/metabolismRNA, Messenger/metabolismSeverity of Illness IndexSignal Transduction/physiologySynovial Membrane/metabolism/pathology
PMID: 19248109
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Research groups Biologie des cytokines de la famille de l'interleukine-1 (1022)
Mécanisme de l'inflammation articulaire (44)
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PALMER-LOURENCO, Gaby et al. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. In: Arthritis and rheumatism, 2009, vol. 60, n° 3, p. 738-49. doi: 10.1002/art.24305 https://archive-ouverte.unige.ch/unige:1815

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Deposited on : 2009-05-28

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