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The PDE4 Inhibitor Rolipram Prevents NF-B Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells¹

Roxane Hervé^*,, Thomas Schmitz^*,,, Danièle Evain-Brion^*,, Dominique Cabrol^*,,, Marie-Josèphe Leroy^*, and Céline Méhats^2,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité 767, Paris, France; Université Paris Descartes, Paris, France; and Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Maternité Port-Royal, Paris, France

Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF- when stimulated by LPS. The transcription factor NF-B is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-. LPS induces the nuclear translocation of the NF-B p65 subunit and the activation of three different NF-B complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF- production and the activation of the three NF-B complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by March of Dimes Birth Defects Foundation Grant 6-FY03-6 and is integrated in the European Preterm Labour Group.

² Address correspondence and reprint requests to Dr Céline Méhats, Institut National de la Santé et de la Recherche Médicale, Unité 767, Faculté de Pharmacie 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France. E-mail address: celine.mehats{at}inserm.fr

³ Abbreviations used in this paper: PDE, phosphodiesterase; CK7, cytokeratin 7.