Our data suggest that during most of human pregnancy, when myometrial cells are PR-B dominant, progesterone promotes myometrial quiescence through PR-B-mediated antiinflammatory actions. At parturition, the rise in PR-A expression promotes labor by inhibiting the antiinflammatory actions of PR-B and stimulating proinflammatory gene expression in response to progesterone.
Endometriotic lesions and eutopic endometrium from women with endometriosis are uniform in a PR-A-dominant state. The data suggest that menstrual efflux of a PR-A-dominant endometrial tissue into the peritoneal cavity may play a role in the pathophysiology of endometriosis.
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.
Estrogens are thought to promote labor by increasing the expression of pro-contraction genes in myometrial cells. The specific estrogen receptors ((ERs: ERa and ERb (also known as ESR1 and ESR2)) and G protein-coupled receptor 30 (GPR30; also known as G protein-coupled estrogen receptor 1)) and signaling pathways that mediate these actions are not clearly understood. In this study, we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol (E 2 ) modulates expression of the gene encoding the oxytocin receptor (OXTR), a major pro-contraction protein. Using quantitative RT-PCR, we found that ERa and GPR30 mRNAs were expressed in the human pregnant myometrium while ERb mRNA was virtually undetectable. While mRNA encoding ERa was the predominant ER transcript in the pregnant myometrium, ERa protein was largely undetectable in myometrial tissue by immunoblotting. Pharmacological inhibition of 26S proteasome activity increased ERa protein abundance to detectable levels in term myometrial explants, however, indicating rapid turnover of ERa protein by proteasomal processing in the pregnant myometrium. E 2 stimulated rapid extranuclear signaling in myometrial explants, as evidenced by increased extracellularly regulated kinase (ERK1/2) phosphorylation within 10 min. This effect was inhibited by pre-treatment with an ER antagonist, ICI 182 780, indicating the involvement of ERa. Inhibition of ERK signaling abrogated the ability of E 2 to stimulate OXTR gene expression in myometrial explants. We conclude that estrogenic actions in the human myometrium during pregnancy, including the stimulation of contraction-associated gene expression, can be mediated by extranuclear signaling through ERa via activation of the ERK/mitogen-activated protein kinase pathway.
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