We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Inhibitors of Mitogen-Activated Protein Kinases downregulate COX-2 Expression in Human Chondrocytes.
- Authors
Nieminen, Riina; Leinonen, Sari; Lahti, Aleksi; Vuolteenaho, Katriina; Jalonen, Ulla; Kankaanranta, Hannu; Goldring, Mary B.; Moilanen, Eeva
- 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.
- Subjects
PROSTAGLANDINS; CYCLOOXYGENASE 2; MITOGEN-activated protein kinases; MITOGENS; PROTEIN kinases
- Publication
Mediators of Inflammation, 2005, Vol 2005, Issue 5, p249
- ISSN
0962-9351
- Publication type
Article
- DOI
10.1155/MI.2005.249