title: Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells.
abstract: The steroid hormone progesterone acting via the nuclear progesterone receptor (PR) isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), is essential for the maintenance of uterine quiescence during pregnancy. Inhibition of PR signaling augments uterine contractility and induces labor. Human parturition is thought to be triggered by modulation of PR signaling in myometrial cells to induce a functional progesterone withdrawal. One mechanism for functional progesterone withdrawal is increased abundance of PR-A, which decreases progesterone responsiveness by inhibiting the transcriptional activity of PR-B. Human parturition also involves tissue-level inflammation within the myometrium. This study examined the control of PR-A abundance and transrepressive activity in myometrial cells and the role of the inflammatory stimuli in the form of interleukin-1β (IL-1β) and lipopolysaccharide (LPS) in these processes. We found that abundance of PR-A was markedly increased by progesterone and by exposure to IL-1β and LPS via posttranslational mechanisms involving increased PR-A protein stability. In contrast, progesterone decreased abundance of PR-B by increasing its rate of degradation. Together, progesterone and proinflammatory stimuli induced a PR-A-dominant state in myometrial cells similar to that observed in term laboring myometrium. IL-1β and LPS also increased the capacity for PR-A to inhibit the transcriptional activity of PR-B. Taken together, our data suggest that proinflammatory stimuli increase the steady-state levels of PR-A and its transrepressive activity in myometrial cells and support the hypothesis that tissue-level inflammation triggers parturition by inducing PR-A-mediated functional progesterone withdrawal.
authors.affiliation: Departments of Reproductive Biology and.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Peters
authors.affiliation: Departments of Reproductive Biology and.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yi
authors.affiliation: Departments of Reproductive Biology and.
authors.forename: Yelenna
authors.initials: Y
authors.lastname: Skomorovska-Prokvolit
authors.affiliation: Departments of Reproductive Biology and.
authors.forename: Bansari
authors.initials: B
authors.lastname: Patel
authors.affiliation: Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; and.
authors.forename: Peyvand
authors.initials: P
authors.lastname: Amini
authors.affiliation: Departments of Reproductive Biology and.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Tan
authors.affiliation: Departments of Reproductive Biology and.|Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; and.|Department of Obstetrics and Gynecology, University Hospitals of Cleveland Medical Center, Cleveland, Ohio 44106.
authors.forename: Sam
authors.initials: S
authors.lastname: Mesiano
mesh_terms: D002460:Cell Line; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D009215:Myometrium / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014590:Uterine Contraction
chemical_list: D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D011374:Progesterone