Alternative p38 MAPKs Are Essential for Collagen-Induced Arthritis

Objective. The role of most p38 MAPK isoforms in inflammatory arthritis is not known. This study was undertaken to evaluate p38 gamma and p38 delta deficiency in the collagen-induced arthritis (CIA) model. Methods. Wild-type, p38 gamma(-/-), p38 delta(-/-), and p38 gamma/delta(-/-) mice were immunized with chicken type II collagen, and disease activity was evaluated by semi-quantitative scoring and histologic assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anticollagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38 MAPK isoform expression in joints were determined by quantitative polymerase chain reaction. Results. Compound p38 gamma and p38 delta deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38 gamma or p38 delta had an intermediate effect. Joint damage was minimal in arthritic p38 gamma/delta(-/-) mice compared with wild-type mice. The p38 gamma/delta(-/-) mice had lower levels of pathogenic anticollagen antibodies and interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha than controls. In vitro T cell assays showed reduced proliferation, interferon-gamma (IFN gamma) production, and IL-17 production by lymph node cells from p38 gamma/delta(-/-) mice. IL-17 and IFN gamma messenger RNA expression in joints was significantly inhibited in p38 gamma/gamma delta(-/-) mice. Wild-type chimeric mice with p38 gamma/delta-/- bone marrow did not show decreased CIA. Conclusion. Reduced disease severity in p38 gamma/delta(-/-) mice was associated with lower cytokine production and anticollagen antibody responses than in controls, indicating that p38 gamma and p38 delta are crucial regulators of inflammatory joint destruction in CIA. Our findings indicate that p38 gamma and p38 delta are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.