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Regulation of the Endothelin/Endothelin Receptor System by Interleukin-1ß in Human Myometrial Cells

Institut National de la Santé et de la Recherche Médicale Unité 427 Paris (M.B.-F., C.M., E.D., S.O., D.C., M.-J.L.), Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, F-75270 Paris cedex 06, France; and Institut National de la Santé et de la Recherche Médicale Unité 709 Paris (R.R.) and Maternité Port-Royal (D.C.), Hôpital Cochin Assistance Publique-Hôpitaux de Paris, Université René Descartes, F-75014 Paris, France

Address all correspondence and requests for reprints to: Michelle Breuiller-Fouché, Institut National de la Santé et de la Recherche Médicale Unité 427 Paris, F-75270 cedex 06 France; or Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 4 Avenue de l’Observatoire, F-75006 Paris, France. E-mail: breuiller-fouche{at}cochin.inserm.fr.

Proinflammatory cytokines produced at the fetomaternal interface, such as IL-1ß, have been implicated in preterm and term labor. The present study was performed to evaluate the influence of IL-1ß on the endothelin (ET)/ET receptor system in human myometrial cells. We report that myometrial cells under basal conditions not only respond to but also secrete ET-1, one of the main regulators of uterine contractions. Prolonged exposure of the cells to IL-1ß led to a decrease in prepro-ET-1 and ET-3 mRNA correlated with a decrease in immunoreactive ET-1 and ET-3 levels in the culture medium. Whereas ETA receptor expression at both protein and mRNA levels was not affected by IL-1ß treatment, we demonstrated an unexpected predominance of the ETB receptor subtype under this inflammatory condition. Whereas the physiological function of ETB remains unclear, we confirmed that only ETA receptors mediate ET-1-induced myometrial cell contractions under basal conditions. By contrast, prolonged exposure of the cells to IL-1ß abolished the contractile effect induced by ET-1. Such a regulation of IL-1ß on the ET release and the balance of ETA to ETB receptors leading to a loss of ET-1-induced myometrial cell contractions suggest that complex regulatory mechanisms take place to constraint the onset of infection-induced premature contractions.

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