Inhibitors of Mitogen-Activated Protein KinasesDownregulate COX-2 Expression in Human Chondrocytes

[摘要] Inducible prostaglandin synthase (cyclooxygenase-2, COX-2) isexpressed in rheumatoid and osteoarthritic cartilage and produceshigh amounts of proinflammatory prostanoids in the joint. In thepresent study we investigated the effects of the inhibitors ofmitogen-activated protein kinase (MAPK) pathways Erk1/2, p38, andJNK on COX-2 expression and prostaglandin E2(PGE2)production in human chondrocytes. Proinflammatory cytokineIL-1βcaused a transient activation of Erk1/2, p38, and JNKin immortalized human T/C28a2 chondrocytes and that was followedby enhanced COX-2 expression and PGE2production. PD98059 (aninhibitor of Erk1/2 pathway) suppressed IL-1-induced COX-2expression and PGE2production in a dose-dependent manner,and seemed to have an inhibitory effect on COX-2 activity.SB203580 (an inhibitor of p38 pathway) but not its negativecontrol compound SB202474 inhibited COX-2 protein and mRNAexpression and subsequent PGE2synthesis at micromolar drugconcentrations. SP600125 (a recently developed JNK inhibitor) butnot its negative control compoundN1-methyl-1,9-pyrazolanthrone downregulated COX-2 expressionand PGE2formation in a dose-dependent manner. SP600125 didnot downregulate IL-1-induced COX-2 mRNA expression when measured2 h after addition of IL-1βbut suppressed mRNA levelsin the later time points suggesting post-transcriptionalregulation. Our results suggest that activation of Erk1/2, p38,and JNK pathways belongs to the signaling cascades that mediate theupregulation of COX-2 expression and PGE2production in humanchondrocytes exposed to proinflammatory cytokine IL-1β.

[学科分类] 生理学与病理学