AP-1 and NF-κB regulation in rheumatoid arthritis and murine collagen-induced arthritis

Objective To determine the expression and regulation of nuclear transcription factors AP-I and NF-kappa B in rheumatoid arthritis and in collagen-induced arthritis in mice. Methods AP-1 and NF-kappa B expression and function a ere determined in RA, OA and normal: synovial tissue by electrophoretic mobility shift assay (EMSA) and immunohistochemistry. The kinetics of transcription factor expression were then examined in collagen-induced arthritis (CIA) in mice. EMSAs a ere performed with the nuclear extracts obtained from paws of CLA mice from 10 to 45 d after immunization to determine AP-1 and NF-kappa B binding activity. The expression of collagenase-3 (MMP13) and stromelysin (MMP3) mRNA was examined by northern blot analysis. Results Immunohistochemistry showed that NF-kappa B expression was increased in both RA and OA synovial intimal lining. AP-1 components Jun and Fos were also present in the intimal Lining and nas significantly greater in RA than OA, The DNA binding activities of both AP-I and NF-kappa B were significantly higher RA patients compared with OA. In CIA, AP-1 and NF-kappa B expression increased by day 20, which was 1-2 weeks before onset of clinical arthritis. However, collagenase and stromelysin gene expression did not increase until day 35, Conclusion The DNA binding activity of AP-1 and NF-kappa B are markedly increased in both CIA and RA, In CIA, activation of AP-I and NF-kappa B precede both clinical arthritis and metalloproteinase gene expression. NF-kappa B expression correlated better than AP-1 with metalloproteinase expression.