Inhibitors of Mitogen-Activated Protein Kinases Downregulate COX-2 Expressionin Human Chondrocytes

摘要

Inducible prostaglandin synthase (cyclooxygenase-2, COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces high amounts of proinflammatory prostanoids in the joint. In the present study we investigated the effects of the inhibitors of mitogen-activated protein kinase (MAPK) pathways Erk1/2, p38, and JNK on COX-2 expression and prostaglandin E2 (PGE2) production in human chondrocytes. Proinflammatory cytokine IL-1β caused a transient activation of Erk1/2, p38, and JNK in immortalized human T/C28a2 chondrocytes and that was followed by enhanced COX-2 expression and PGE2 production. PD98059 (an inhibitor of Erk1/2 pathway) suppressed IL-1-induced COX-2 expression and PGE2 production 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 negative control compound SB202474 inhibited COX-2 protein and mRNA expression and subsequent PGE2 synthesis at micromolar drug concentrations. SP600125 (a recently developed JNK inhibitor) butnot its negative control compound N¹-methyl-1,9-pyrazolanthronedownregulated COX-2 expression and PGE2 formation in a dose-dependent manner. SP600125 didnot downregulate IL-1-induced COX-2 mRNA expression when measured2 h after addition of IL-1β but 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 PGE2 production in humanchondrocytes exposed to proinflammatory cytokine IL-1β.