Mediators of Inflammation 
Volume 2005 (2005), Issue 5, Pages 249-255
doi:10.1155/MI.2005.249

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

Riina Nieminen,1 Sari Leinonen,1 Aleksi Lahti,1 Katriina Vuolteenaho,1 Ulla Jalonen,1 Hannu Kankaanranta,1 Mary B. Goldring,2 and Eeva Moilanen1

 1The Immunopharmacology Research Group, Medical School, University of Tampere, and Tampere University Hospital, Research Unit, Tampere 33014, Finland
2Rheumatology Division, Beth Israel Deaconess Medical Center and New England Baptist Bone & Joint Institute, Harvard Institutes of Medicine, Boston 02215, MA, USA
Received 23 June 2005; Accepted 5 July 2005

Abstract

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) but not its negative control compound N1-methyl-1,9-pyrazolanthrone downregulated COX-2 expression and PGE2 formation in a dose-dependent manner. SP600125 did not downregulate IL-1-induced COX-2 mRNA expression when measured 2 h after addition of IL-1β but suppressed mRNA levels in the later time points suggesting post-transcriptional regulation. Our results suggest that activation of Erk1/2, p38, and JNK pathways belongs to the signaling cascades that mediate the upregulation of COX-2 expression and PGE2 production in human chondrocytes exposed to proinflammatory cytokine IL-1β.