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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‐1β (IL‐1β, 10 ng ml−1) for 1 to 24 h. Cyclooxygenase‐2 (COX‐2) mRNA and protein were rapidly induced, with expression sustained at 24 h. 2 Cycloheximide (10 μg ml−1, 6 h) blocked IL‐1β‐induced COX‐2 protein expression and super‐induced COX‐2 mRNA expression. Induction of COX‐2 mRNA and protein was blocked by dexamethasone (1 μm, 6 h). 3 IL‐1β‐induced COX‐2 expression was accompanied by a 3‐fold increase of prostaglandin E2 release into the culture medium. 4 IL‐1β induced a transient (5–30 min) activation of p42/44 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 SB 203580 (10 μm, 5–30 min). 5 COX‐2 protein expression detected after 6 h IL‐1β stimulation was blocked by SB 203580 (10 μm). Exposure of HMSMCs to 10 ng ml−1 IL‐1β 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 μm) during only the first 30 min of IL‐1β 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‐1β‐stimulated COX‐2 expression in human myometrial smooth muscle cells. Induction of COX‐2 by IL‐1β 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.