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

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Abstract
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.

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