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* Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom;
Department of Microbiology, Tokyo Medical and Dental University, Tokyo, Japan;
Institüt für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; and
Institute of Nephrology and
¶
Department of Rheumatology, University of Wales College of Medcine, Cardiff, Wales, United Kingdom
Studies in IL-6-deficient (IL-6-/-) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6-/- mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.
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