AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis.
OBJECTIVE
To determine the expression and regulation of nuclear transcription factors AP-1 and NF-kappaB in rheumatoid arthritis and in collagen-induced arthritis in mice.


METHODS
AP-1 and NF-kappaB expression and function were 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 were performed with the nuclear extracts obtained from paws of CIA mice from 10 to 45d after immunization to determine AP-1 and NF-kappaB binding activity. The expression of collagenase-3 (MMP13) and stromelysin (MMP3) mRNA was examined by northern blot analysis.


RESULTS
Immunohistochemistry showed that NF-kappaB 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-kappaB were significantly higher RA patients compared with OA. In CIA, AP-1 and NF-kappaB 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.


CONCLUSIONS
The DNA binding activity of AP-1 and NF-kappaB are markedly increased in both CIA and RA. In CIA, activation of AP-1 and NF-kappaB precede both clinical arthritis and metalloproteinase gene expression. NF-kappaB expression correlated better than AP-1 with metalloproteinase expression.
Han
Z
Z
Division of Rheumatology, UCSD School of Medicine, La Jolla, CA 92093-0656, USA.
Boyle
D L
DL
Manning
A M
AM
Firestein
G S
GS
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D003094:Collagen; D017364:Collagenases / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D008297:Male; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D013583:Synovial Membrane / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051996:Transcription Factor RelA
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3