AP-1 and NF-kB Regulation in Rheumatoid Arthritis and Murine Collagen-Induced Arthritis

Publisher Website
Google Scholar
Abstract
Objective To determine the expression and regulation of nuclear transcription factors AP-1 and NF-KB in rheumatoid arthritis and in collagen-induced arthritis in mice. Methods AP-1 and NF-KB expression and function were determined in RA, OA and normal synovial tissue by electrophoretic mobility shift assay (EMSA) and immunohis-tochemistry. The kinetics of transcription factor expression were then examined in collagen-induced arthritis (CIA) in mice. EMSAs were performed with the nuclear extracts obtained from paws of CIA mice from 10 to 45 d after immunization to determine AP-1 and NF-KB binding activity. The expression of collagenase-3 (MMP13) and stromelysin (MMP3) mRNA was examined by northern blot analysis. Results Immunohistochemistry showed that NF-KB 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 was significantly greater in RA than OA. The DNA binding activities of both AP-1 and NF-KB were significantly higher RA patients compared with OA. In CIA, AP-1 and NF-KB 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-KB are markedly increased in both CIA and RA. In CIA, activation of AP-1 and NF-KB precede both clinical arthritis and metalloproteinase gene expression. NF-KB expression correlated better than AP-1 with metalloproteinase expression.