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Interleukin-1ß Induces Phosphodiesterase 4B2 Expression in Human Myometrial Cells through a Prostaglandin E₂- and Cyclic Adenosine 3',5'-Monophosphate-Dependent Pathway

INSERM, U-361, Maternité Port Royal Cochin, Université Paris V, René Descartes, 75014 Paris, France

Address all correspondence and requests for reprints to: Dr. Marie-Josèphe Leroy, INSERM, U-361, Pavillon Baudelocque, 123 boulevard Port Royal, 75014 Paris, France. E-mail: leroy-zamia{at}cochin.inserm.fr.

Abstract

Intrauterine infections are important etiological factors of preterm labor. They trigger an increase in proinflammatory cytokines, in particular IL-1ß, that induces a cascade of events resulting in the production of potent effectors of myometrial contractility, such as the prostaglandin E₂ (PGE₂). Within the smooth muscle cells, contractility is under the control of cAMP content, partly regulated by cAMP-phosphodiesterase 4 (PDE4), the predominant family of PDEs expressed in human myometrium. In the present study, using a model of inflammation of human myometrial cells in culture, we demonstrated that exposing the cells to IL-1ß resulted in a significant up-regulation of PDE4 activity through an increase in PDE4B2 mRNA and protein levels. The IL-1ß-induced PDE4 activity occurs after an increase in PGE₂ production and subsequent cAMP augmentation. Pretreatment with indomethacin or NS 398 completely blocked this long-term effect of IL-1ß, revealing a PGE₂-dependent pathway. Accordingly, our results demonstrated that the PDE4B2 variant can participate in the regulation of the inflammatory reaction that occurs at term or in preterm labor and leads to myometrial contractions. Knowing the myorelaxant effect of PDE4 inhibitors and the implication of the PDE4B2 in the inflammatory process, this isoform may be an appropriate target for discovering antiinflammatory drugs to manage infection-induced preterm deliveries.

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