Decreased collagen‐induced arthritis severity and adaptive immunity in MKK‐6–deficient mice

Abstract Objective The MAPK kinases MKK‐3 and MKK‐6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK‐3 or MKK‐6 deficiency inhibits K/BxN serum–induced arthritis. However, the role of these kinases in adaptive immunity–dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK‐3 and MKK‐6 deficiency in the collagen‐induced arthritis (CIA) model. Methods Wild‐type (WT), MKK‐3 –/– , and MKK‐6 –/– mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro–computed tomography. Serum anticollagen antibody levels were quantified by enzyme‐linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction. Results MKK‐6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK‐3 had an intermediate effect. Joint damage was minimal in arthritic MKK‐6 –/– mice and intermediate in MKK‐3 –/– mice compared with WT mice. MKK‐6 –/– mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK‐3 –/– mice. In vitro T cell assays showed reduced proliferation and interleukin‐17 (IL‐17) production by lymph node cells from MKK‐6 –/– mice in response to type II collagen. Gene expression of synovial IL‐6, MMP‐3, and MMP‐13 was significantly inhibited in MKK‐6–deficient mice. Conclusion Reduced disease severity in MKK‐6 –/– mice correlated with decreased anticollagen antibody responses, indicating that MKK‐6 is a crucial regulator of inflammatory joint destruction in CIA. MKK‐6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA.