Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1β:: involvement of p38 mitogen-activated protein kinase

1. Human myometrial smooth muscle cells (HMSMCs) in culture were exposed to recombinant human interleukin-1 beta (IL-1 beta, 10 ng ml(-1)) for 1 to 24 h. Cyclooxygenase-2 (COX-2) mRNA and protein were rapidly induced, with espression sustained at 24 h. 2. Cycloheximide (10 mu g ml(-1) 6 h) blocked IL-1 beta-induced COX-2 protein expression and super-induced COX-2 mRNA expression. Induction of COX-2 mRNA and protein was blocked by dexamethasone (1 mu m, 6 h). 3. IL-1 beta-induced COX-2 expression was accompanied by a 3-fold increase of prostaglandin E-2 release into the culture medium. 4. IL-1 beta induced a transient (5-30 min) activation of p42/4 1 and p38 mitogen-activated protein kinase (MAPK) enzymes in HMSMCs. Activity of p38 MAPK was monitored by in gel activity of its substrate MAP kinase-activated protein kinase-2 (MAPKAP kinase-2). Induction of MAPKAP kinase-2 activity was prevented by the p38 MAPK inhibitor SE 203580 (10 mu m, 5-30 min). 5. COX-2 protein expression detected after 6 h IL-1 beta stimulation was blocked by SE 203580 (10 mu m). Exposure of HMSMCs to 10 ng ml(-1) IL-1 beta for only 30 min induced a level of COX-2 protein expression at 6 h culture similar to that detected in cells exposed to the cytokine for 6 h. 6. Exposure of cells to SB 203580 (10 mu m) during only the first 30 min of IL-1 beta stimulation was effective in blocking COX-2 protein expression assayed after 6 h in culture. 7. This study has established that a transient activation of the p38 MAPK cascade is involved in IL-1 beta-stimulated COX-2 expression in human myometrial smooth muscle cells. Induction of COX-2 by IL-1 beta in HMSMCs provides support for the hypothesis that autocrine prostaglandin signalling in the myometrium, initiated by elevated intrauterine cytokine concentrations, plays a role in regulating myometrial contractility during labour.