title: ADRB3 adrenergic receptor is a key regulator of human myometrial apoptosis and inflammation during chorioamnionitis.
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 microg/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.
authors.affiliation: Laboratoire de Physiologie et Pharmacologie Cardiovasculaires Expérimentales (LPPCE, EA279, IFR Santé-STIC), Faculté de Médecine, Université de Bourgogne, Dijon, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Lirussi
authors.forename: Zo
authors.initials: Z
authors.lastname: Rakotoniaina
authors.forename: Siham
authors.initials: S
authors.lastname: Madani
authors.forename: Françoise
authors.initials: F
authors.lastname: Goirand
authors.forename: Michelle
authors.initials: M
authors.lastname: Breuiller-Fouché
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Leroy
authors.forename: Paul
authors.initials: P
authors.lastname: Sagot
authors.forename: John J
authors.initials: JJ
authors.lastname: Morrison
authors.forename: Monique
authors.initials: M
authors.lastname: Dumas
authors.forename: Marc
authors.initials: M
authors.lastname: Bardou
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D017209:Apoptosis / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D002821:Chorioamnionitis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D001565:Benzoates; D016207:Cytokines; D008070:Lipopolysaccharides; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; C521336:ethyl 4-(4-((2-hydroxy-3-(4-hydroxy-3-((methylsulfonyl)amino)phenoxy)propyl)amino)cyclohexyl)benzoate