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.