Inhibitors of mitogen-activated protein kinases downregulate COX-2 expression in human chondrocytes

Mediators Inflamm. 2005 Oct 24;2005(5):249-55. doi: 10.1155/MI.2005.249.


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-1beta 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-1beta 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-1beta.

MeSH terms

  • Anthracenes / pharmacology
  • Chondrocytes / metabolism
  • Cyclooxygenase 2 / metabolism*
  • Dinoprostone / biosynthesis*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Activation / genetics*
  • Enzyme Inhibitors / pharmacology*
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-1 / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Pyridines / pharmacology
  • RNA, Messenger / metabolism
  • Signal Transduction


  • Anthracenes
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Interleukin-1
  • Pyridines
  • RNA, Messenger
  • pyrazolanthrone
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinases
  • Dinoprostone
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one