Han Z, Boyle D L, Aupperle K R, Bennett B, Manning A M, Firestein G S
Division of Rheumatology, University of California at San Diego School of Medicine, La Jolla, California, USA.
J Pharmacol Exp Ther. 1999 Oct;291(1):124-30.
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 microM, a concentration that only inhibits p38) had no significant effect on IL-1-induced collagenase expression in RA FLS whereas 25 microM (which inhibits p38, JNK2, and c-raf) blocked collagenase mRNA accumulation. IL-1-stimulated AP-1 binding was also inhibited by 25 microM 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.
通过研究丝裂原活化蛋白激酶的调节以及成纤维样滑膜细胞（FLS）中胶原酶基因的表达，对类风湿关节炎（RA）关节破坏的潜在机制进行了研究。丝裂原活化蛋白激酶的三个主要家族 [p38、Jun N端激酶（JNK）和细胞外信号调节激酶（ERK）] 在RA和成骨性关节炎（OA）的FLS中组成性表达。在白细胞介素-1（IL-1）刺激后，p38和ERK1/2在RA和OA的FLS中均易于磷酸化。IL-1刺激后，JNK在RA的FLS中磷酸化，但在OA的FLS中未磷酸化。逆转录-聚合酶链反应研究表明，JNK2是FLS表达的JNK家族的主要亚型。胶原酶基因表达的Northern印迹分析表明，IL-1刺激后，RA的FLS中胶原酶mRNA明显多于OA的FLS。用p38/JNK抑制剂SB 203580评估了JNK和p38激酶的作用。低浓度的SB 203580（1 microM，仅抑制p38的浓度）对RA的FLS中IL-1诱导的胶原酶表达无显著影响，而25 microM（抑制p38、JNK2和c-raf）则阻断了胶原酶mRNA的积累。25 microM的SB 203580也抑制了RA的FLS中IL-1刺激的AP-1结合。这些研究表明，OA和RA的FLS具有不同的JNK磷酸化模式，这可能导致RA中胶原酶基因表达增强。
