PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation: PDE4 inhibition blocks preterm delivery

• Published in: The Journal of immunology (1950) 2007-01, Vol.178 (2), p.1115-21
• Main Authors: Schmitz, Thomas, Souil, Evelyne, Hervé, Roxane, Nicco, Carole, Batteux, Frédéric, Germain, Guy, Cabrol, Dominique, Evain-Brion, Danièle, Leroy, Marie-Josèphe, Méhats, Céline
• Format: Article
• Language: English
• Subjects: cell activation; Gynecology and obstetrics; Human health and pathology; Immunology; inflammation; Life Sciences; Reproductive immunology; rodent
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.178.2.1115

The aim of this study was to explore the anti-inflammatory properties of phosphodiesterase-4 (PDE4) inhibitors in vivo and their potential ability to prevent inflammation-induced preterm delivery. Indeed, intrauterine inflammation is the major etiology of very preterm delivery, the leading cause of neonatal mortality and morbidity. Intrauterine injection of Escherichia coli LPS in 15-day-pregnant mice induced an increase of PDE4 activity and PDE4B expression at the maternofetal interface, a rise of amniotic fluid levels of TNF-alpha, IL-1beta, IL-6, and IL-10 and provoked massive preterm delivery and fetal demise. Selective PDE4 inhibition by rolipram prevented the rise in the proinflammatory cytokines. Following the nuclear translocation of the transcription factor NFkappaB, as a marker of cellular activation after the inflammatory challenge, showed a time-dependent sequential activation of the gestational tissues, from the uterine mesometrial to the fetal compartment, particularly in the glycogen-trophoblastic cells of the placenta. This activation was disrupted by PDE4 inhibition, and inflammation-induced preterm delivery and fetal demise were prevented. PDE4 selective inhibitors may thus represent a novel effective treatment to delay inflammation-induced preterm delivery and to prevent adverse outcomes in infants.