Oxytocin activates mitogen-activated protein kinase and up-regulates cyclooxygenase-2 and prostaglandin production in human myometrial cells

被引:78
作者
Molnár, M
Rigo, J
Romero, R
Hertelendy, F
机构
[1] Semmelweis Univ, Inst Pathophysiol, H-1085 Budapest, Hungary
[2] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary
[3] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA
[4] NICHHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA
[5] St Louis Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63117 USA
[6] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63117 USA
[7] St Marys Hlth Ctr, St Louis, MO USA
关键词
cyclooxygenase-2; oxytocin; prostaglandins; mitogen-activated protein kinase; signal transduction; human myometrial cells;
D O I
10.1016/S0002-9378(99)70434-5
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
OBJECTIVE: The objective of our study was to test the hypothesis that oxytocin promotes prostaglandin production by up-regulating cyclooxygenase-2 via activation of mitogen-activated protein kinase cascade in human myometrial cells. STUDY DESIGN: Confluent cultures of human myometrial cells obtained from uterine specimens of premenopausal women undergoing hysterectomy were serum starved for 48 hours before oxytocin stimulation. Prostacyclin levels, as 6-keto-prostaglandin F-1 alpha, were measured by radioimmunoassay, and the cellular cyclooxygenase-2 protein content was determined by Western blot. Mitogen-activated protein kinase activity was assessed by measuring the phosphorylation of myelin basic protein. RESULTS: In a time- and dose-dependent manner oxytocin promoted prostacyclin production in human myometrial cells. Maximal responses were observed after 8 hours of stimulation at a dose of 100 nmol/L. This effect was mainly due to the expression of cyclooxygenase-2 protein. Within 5 minutes oxytocin significantly stimulated mitogen-activated protein kinase, as compared with the expression in untreated controls. The maximal increase in enzyme activity (2.5-fold) was obtained at 45 minutes. A selective inhibitor of mitogen-activated protein kinase activation (PD98059), as well as herbimycin, a tyrosine kinase inhibitor, and the transcriptional blocker actinomycin D, suppressed oxytocin-induced cyclooxygenase-2 expression and prostacyclin production. The stimulatory action of oxytocin was also sensitive to inhibition by pertussis toxin but appeared to be independent of protein kinase C activation. CONCLUSION: Our data indicate a largely unrecognized signal transduction mechanism for oxytocin, involving G-protein-coupled activation of mitogen-activated protein kinase and cyclooxygenase-2 gene expression, leading to increased prostaglandin production in human myometrial cells. This signaling pathway complements the rapid activation of the phosphoinositide cycle and may be responsible for sustained release of prostaglandins in uterine tissues, promoting labor and parturition.
引用
收藏
页码:42 / 49
页数:8
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