IL-21 modulates cytokine levels in murine collagen-induced arthritis and contributes to disease pathology

Background IL-21 is secreted by activated T cells and modulates immune cell functions with both proinflammatory and anti-inflam-matory effects. IL-21 receptor (IL-21R), homologous to IL-2Rβ and IL-4Rα, associates with the gamma common chain upon ligand binding. It was recently described that IL-21R is overexpressed in the inflamed synovial membrane and on leucocytes of rheumatoid arthritis patients. Objective Previously we have shown that blockade of the IL-21 pathway with soluble IL-21R-Fc resulted in a reduction of clinical signs of arthritis in rodent models. To understand potential mechanisms of IL-21 regulation in arthritis, we analyzed serum immuno-globulin levels, and cytokine expression in the paws, serum, and collagen-restimulated splenocytes, in response to IL-21 pathway blockade. Methods Arthritis was induced in DBA/1 male mice with bovine type II collagen. Animals were treated with either soluble mIL-21R-Fc, which neutralizes murine IL-21 bioactivity, with TNFRII-Fc or with control IgG. Spleens from each group of treated mice were cultured in vitro with collagen and assayed for cytokine secretion. Cytokines and anticollagen-specific IgG levels were also measured in the serum by ELISA. Cytokine mRNA levels in the paws were evaluated by quantitative PCR analysis. Results Treatment of mice with IL-21R-Fc or TNFRII-Fc reduced clinical and histological signs of collagen-induced arthritis. IL-6 mRNA in paws and serum IL-6 levels were decreased after IL-21R-Fc treatment. IFNγ mRNA was increased in paws of IL-21R-Fc-treated mice. Collagen-specific spleen cell responses from IL-21R-Fc-treated mice exhibited increased IFNγ and IL-2, and reduced IL-6 and IL-17 levels. Serum levels of total IgG 1 were also reduced in response to IL-21R-Fc treatment. Conclusion These data demonstrate a role for IL-21 in the modulation of collagen-specific T-cell responses and the pathology of arthritis, supporting a rationale for blockade of the IL-21 pathway in rheumatoid arthritis. Background TNFα is a key cytokine in rheumatoid arthritis (RA) physiopathology. We recently demonstrated that a new cationic liposome formulation allowed intravenous delivery of a small interfering RNA (siRNA) targeting TNFα and efficiently restoring the immunological balance in an experiment model of RA. Since 30% of patients do not respond to anti-TNF biotherapies, however, there is a need to develop alternative therapeutic approaches. Objective Strong association of other proinflammatory cytokines with the pathogenesis of RA prompted us to investigate which cytokine other than TNFα could be targeted for therapeutic benefit using RNA interference. Methods Two siRNA sequences were designed for IL-1β, IL-6 and IL-18 proinflammatory cytokines, and their efficacy and specificity were …