Control of Progesterone Receptor-A Transrepressive Activity in Myometrial Cells: Implications for the Control of Human Parturition

Abstract

Uterine quiescence during pregnancy is maintained by progesterone primarily via signaling mediated by the type-B progesterone receptor (PR-B) in myometrial cells. Withdrawal of PR-B-mediated progesterone activity is a principal trigger for labor. One mechanism for PR-B withdrawal is by inhibition of its activity by the type-A PR (PR-A) isoform in myometrial cells. We hypothesized that human parturition involves hormonal interactions that induce the capacity for PR-A to inhibit PR-B in myometrial cells and that pro-inflammatory cytokines are major regulators of this process. We tested this hypothesis in an immortalized human myometrial cell line, hTERT-HM, in which levels of PR-A and PR-B can be experimentally controlled. We found that the capacity for PR-A to repress PR-B, assessed by activity of a transiently transfected reporter DNA controlled by the progesterone response element, and expression of FK506 binding protein 5 ( FKBP5) an endogenous PR-B responsive gene, was increased by serum supplementation and interleukin-1β. In pregnant uterus, FKBP5 was detected exclusively in myometrial cells and its expression decreased with advancing gestation and in association with the onset of labor at term. These findings suggest that in myometrial cells the repressive activity of PR-A on PR-B increases with advancing gestation and is induced by pro-inflammatory cytokines. This may be a key mechanism linking inflammation with the onset of labor.

The Role of Danger Associated Molecular Patterns in Human Fetal Membrane Weakening

“…Animals other than humans and nonhuman primates experience a drop-in progesterone level but this does not appear to happen in the same way in humans (Menon et al, 2016a). In order to increase our understanding of the differences in the mechanism, studies have focused on areas of enquiry that may lead to "functional" progesterone withdrawal, such as the role of prostaglandin receptors (Nadeem et al, 2016;Patel et al, 2018) and the minutiae of inflammation control by cytokine cascades and specific transcription factors (Lappas et al, 2008;Paulesu et al, 2010). Understating the trigger for labor onset is important for us to decipher how this may deviate in patients with PTB.…”

“…These molecules typically have a different specific function during normal cellular activity, but when the cell detects a stress stimulus, they are activated now functioning to signal "the alarm.". Many different molecules are classified as DAMPs, including various heat shock proteins (HSP), extracellular matrix (ECM) breakdown products, and nucleic acid fragments (Table 1; Patel et al, 2018). DAMPs are already known to have a role in a wide range of other diseases with strong inflammatory signatures, such as, autoimmune diseases (Systemic Lupus Erythematosus, Rheumatoid Arthritis), Osteoarthritis, cardiovascular diseases, neurodegenerative diseases and cancer (Roh and Sohn, 2018).…”

Riding the Rhythm of Melatonin Through Pregnancy to Deliver on Time

“…Parturition is triggered when progesterone is functionally withdrawn, PR-B expression decreases, and progesterone receptor A (PR-A) expression increases. This switch causes an increase in procytokine release and initiation of myometrial contractions (60, 61). Later in this review, we further discuss the roles of melatonin in promoting parturition.…”

Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage

“…While isoform switching is ancestral in primates and rodents and thus did not evolve to initiate parturition, there is evidence supporting its role in the initiation of human labor [67,68,[71][72][73][74][75][76][77]. Furthermore, the role of progesterone in the maintenance of pregnancy up to term is supported by studies showing that disruption of progesterone signaling by the PR-A/ PR-B antagonist RU486 at any stage of pregnancy results in myometrial contractions and the initiation of labor in rodents [78][79][80] and primates [64], including humans [81].…”