PT  - JOURNAL ARTICLE
AU  - Zuoning Han
AU  - David L. Boyle
AU  - Karlfried R. Aupperle
AU  - Brydon Bennett
AU  - Anthony M. Manning
AU  - Gary S. Firestein
TI  - Jun N-Terminal Kinase in Rheumatoid Arthritis
DP  - 1999 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 124--130
VI  - 291
IP  - 1
4099  - http://jpet.aspetjournals.org/content/291/1/124.short
4100  - http://jpet.aspetjournals.org/content/291/1/124.full
SO  - J Pharmacol Exp Ther1999 Oct 01; 291
AB  - Potential mechanisms of joint destruction in rheumatoid arthritis (RA) were examined by studying the regulation of mitogen-activated protein kinases and collagenase gene expression in fibroblast-like synoviocytes (FLS). The three main mitogen-activated protein kinase families [p38, Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERKs)] were constitutively expressed in RA and osteoarthritis (OA) FLS. p38 and ERK1/2 were readily phosphorylated in both RA and OA FLS after interleukin-1 (IL-1) stimulation. JNK was phosphorylated in RA FLS but not OA FLS after IL-1 stimulation. Reverse transcription-polymerase chain reaction studies suggested that JNK2 is the major isoform of the JNK family expressed by FLS. Northern blot analysis of collagenase gene expression demonstrated that RA FLS contained significantly more collagenase mRNA than OA FLS after IL-1 stimulation. The roles of JNK and p38 kinase were evaluated with the p38/JNK inhibitor SB 203580. Low concentrations of SB 203580 (1 μM, a concentration that only inhibits p38) had no significant effect on IL-1-induced collagenase expression in RA FLS whereas 25 μM (which inhibits p38, JNK2, and c-raf) blocked collagenase mRNA accumulation. IL-1-stimulated AP-1 binding was also inhibited by 25 μM SB 203580 in RA FLS. These studies suggest that OA and RA FLS have a different pattern of JNK phosphorylation, which might lead to enhanced collagenase gene expression in RA. The American Society for Pharmacology and Experimental Therapeutics