Submitted July 20, 2007
Returned for revision August 21, 2007
Accepted October 19, 2007
Female Reproductive Tract
ADRB3 Adrenergic Receptor Is a Key Regulator of Human Myometrial Apoptosis and Inflammation During Chorioamnionitis
Fréderic Lirussi ,
Zo Rakotoniaina ,
Siham Madani ,
Françoise Goirand ,
Michelle Breuiller-Fouché ,
Marie-Josèphe Leroy ,
Paul Sagot ,
John J. Morrison ,
Monique Dumas ,
and
Marc Bardou *
* To whom correspondence should be addressed. E-mail: marc.bardou{at}u-bourgogne.fr.
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. While there is evidence implicating ADRB receptors in 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 incubating with Escherichia coli Lipopolisaccharide (LPS) the myometrial samples obtained from uncomplicated pregnancies. We observed that, chorioamnionitis was associated with a significant increase in cleaved CASP3 protein expression, and chromatin condensation, which were reproduced experimentally by LPS stimulation (10 µg/ml, 48h). LPS stimulation of normal human myometrium also induced CASP3 transcripts, increased the proapoptotic marker BAX and decreased the antiapoptotic marker BCL2. LPS-induced apoptosis was antagonized by neutralization of secreted TNF by a specific antibody. Furthermore LPS stimulation increased medium culture levels of proinflammatory cytokines, IL6 and IL8. LPS-induced apoptosis and cytokines 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.
Key words:
Immunology •
Pregnancy •
Apoptosis •
Cytokines •
beta-adrenoceptors
