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* Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
Department of Rheumatology, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom;
Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany;
Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom;
¶ Ludwig Cancer Research Institute, Melbourne, Victoria, Australia; and
|| Monash Institute for Medical Research, Clayton, Victoria, Australia
Cytokine control of the synovial infiltrate is a central process in the development of inflammatory arthritis. In this study, we combine genetic approaches and intervention strategies to describe a fundamental requirement for IL-6-mediated STAT3 signaling in orchestrating the inflammatory infiltrate in monoarticular and systemic models of experimental arthritis. STAT3 activation via the common gp130 signal-transducing receptor for all IL-6-related cytokines led to increased retention of neutrophils and T cells within the inflamed synovium, which included STAT3-regulated IL-17A-secreting T cells. Control of leukocyte infiltration was reliant upon IL-6 signaling via its soluble receptor (termed IL-6 trans signaling), as evidenced by selective blockade of this alternative IL-6 signaling pathway using an engineered variant of soluble gp130 (sgp130Fc). This therapeutic intervention led to substantial clinical improvement in mice with emerging or established incidence of systemic arthritis. These data illustrate that IL-6 control of STAT3 is critical for regulating the synovial infiltrate in inflammatory arthritis, and suggest that selective inhibition of IL-6 trans signaling may provide a more refined intervention strategy for blocking IL-6-driven proarthritic activities.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Arthritis Research Campaign and the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB415, Projects B5 and C6).
2 M.A.N. and A.S.W. contributed equally to the experimental work in this study.
3 Address correspondence and reprint requests to Prof. Simon A. Jones, Department of Medical Biochemistry and Immunology, School of Medicine, Tenovus Building, Heath Park, Cardiff University, Cardiff, CF14 4XN, Wales, U.K. E-mail address: JonesSA{at}cf.ac.uk
4 Abbreviations used in this paper: sIL-6R, soluble form of IL-6R; AIA, Ag-induced arthritis; CIA, collagen-induced arthritis; i.a., intra-articular; KO, knockout; mBSA, methylated BSA; OA, osteoarthritis; pY, tyrosine phosphorylated; RA, rheumatoid arthritis; RANKL, receptor activator of NF-
B ligand; sgp130, soluble gp130; WT, wild type.
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