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This Article Full Text Full Text (PDF) [Supplemental Figure] All Versions of this Article: 78/3/497    most recent biolreprod.107.064444v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lirussi, F. Articles by Bardou, M. PubMed PubMed Citation Articles by Lirussi, F. Articles by Bardou, M. Agricola Articles by Lirussi, F. Articles by Bardou, M.

ADRB3 Adrenergic Receptor Is a Key Regulator of Human Myometrial Apoptosis and Inflammation During Chorioamnionitis¹

Laboratoire de Physiologie et Pharmacologie Cardiovasculaires Expérimentales (LPPCE, EA279, IFR Santé-STIC),³ Faculté de Médecine, Université de Bourgogne, 21079 Dijon, France Unité INSERM U767,⁴ Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 75006 Paris, France Department of Obstetrics and Gynecology,⁵ CHU du Bocage Dijon, 21079 Dijon, France Department of Obstetrics and Gynaecology,⁶ Clinical Science Institute, National University of Ireland Galway, University College Hospital Galway, Galway, Ireland Centre d'Investigation Clinique,⁷ Unité de Pharmacologie Clinique, 21000 Dijon, France

ABSTRACT

The pathophysiology underlying preterm labor triggered by inflammatory conditions such as chorioamnionitis remains largely unclear. It has already been suggested that beta-3 adrenergic (ADRB3) agonists might be of interest in the pharmacological management of preterm labor. Although there is evidence implicating ADRB receptors in the control of inflammation, there are minimal data relating specifically to ADRB3. To explore the cellular consequences of chorioamnionitis and detect apoptosis, we first performed immunostaining and Western blot experiments on human myometrial samples obtained from women with confirmed chorioamnionitis. We then developed an in vitro model of chorioamnionitis by incubating the myometrial samples obtained from uncomplicated pregnancies with Escherichia coli lipopolysaccharide (LPS). We observed that chorioamnionitis was associated with a significant increase in cleaved CASP3 protein expression, as well as chromatin condensation, which were reproduced experimentally by LPS stimulation (10 µg/ml, 48 h). Lipopolysaccharide stimulation of normal human myometrium also induced CASP3 transcripts, increased the proapoptotic marker BAX, and decreased the antiapoptotic marker BCL2. Lipopolysaccharide-induced apoptosis was antagonized by neutralization of secreted tumor necrosis factor by a specific antibody. Furthermore, LPS stimulation increased medium culture levels of proinflammatory cytokines interleukin 6 (IL6) and IL8. Lipopolysaccharide-induced apoptosis and cytokine production were prevented by the new and potent ADRB3 agonist SAR150640 in a concentration-dependent manner. SAR150640 by itself did not exhibit any effect on apoptosis or cytokine production in control tissues. This study shows that chorioamnionitis is associated with apoptosis of human myometrial cells. It emphasizes the potential therapeutic interest of ADRB3 agonists in the field of preterm labor and other inflammatory conditions.

apoptosis, bacterial infection, beta-adrenoceptors, cytokines, immunology, inflammation, lipopolysaccharide, pregnancy

¹Supported by a grant from the Conseil Régional de Bourgogne and the Centre Hospitalier Régional et Universitaire de Dijon. This research is integrated in the European Preterm Labour Group.

Correspondence: ²LPPCE, Faculté de Médecine 7, bd Jeanne d'Arc, BP 87900, 21079 Dijon, France. FAX: 33 380 393 293; e-mail: marc.bardou{at}u-bourgogne.fr