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

IL-21 is secreted by activated T cells and modulates immune cell functions with both proinflammatory and anti-inflammatory 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.

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 immunoglobulin levels, and cytokine expression in the paws, serum, and collagen-restimulated splenocytes, in response to IL-21 pathway blockade.

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.

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 IgG₁ were also reduced in response to IL-21R-Fc treatment.

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.