Enhanced Human Decidual Cell–Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal

Abstract

Sustained plasma progesterone (P4) levels suggest initiation of human term labor by functional P4 withdrawal, reflecting reduced progesterone receptor (PR) and/or glucocorticoid receptor (GR) expression or activity. The steroid-induced immunophilin cochaperone FKBP51 inhibits PR- and GR-mediated transcription, suggesting a labor-initiating role. Gestational age-matched decidual sections were immunostained for FKBP51 and decidual cell (DC) and interstitial trophoblast (IT) markers, vimentin and cytokeratin, respectively. Term DC cultures were incubated with vehicle (control), estradiol (E2) with or without medroxyprogesterone acetate, dexamethasone (Dex), or Organon 2058. FKBP51 histologic scoring was significantly higher in DC nuclei during labor versus prelabor decidua, whereas FKBP51 immunostaining was undetected in interstitial trophoblasts (P < 0.05). In term DC cultures, E2 + medroxyprogesterone acetate or E2 + Dex enhanced FKBP51 expression (P < 0.01), whereas E2 + Organon 2058 inhibited PR expression (P < 0.05), and E2 + Dex inhibited GR expression (P < 0.05). Unlike term DCs, FKBP51 was undetected in control or Dex-treated cultured third-trimester trophoblasts. Electrophoretic mobility shift assays revealed that FKPB51 overexpression or silencing in cultured DCs altered PR-DNA binding. Increased FKBP51 levels in term DCs during labor complement our prior in situ observations of significantly lower PR in labor versus prelabor DCs. In a milieu of sustained plasma P4 levels, these reciprocal changes will amplify functional P4 withdrawal in DCs via FKBP51-mediated PR resistance coupled with declining PR levels, whereas the lack of FKBP51 expression in interstitial trophoblasts suggests unopposed constitutive GR action.

Decidual cell FKBP51–progesterone receptor binding mediates maternal stress–induced preterm birth

“…The failure of such therapy, coupled with observations that PR antagonist therapy ± prostaglandins induce labor at all gestational ages (51), indicates that functional P4 withdrawal mediated at the level of the PR triggers human labor. This hypothesis is further supported by our previous findings that term labor is associated with reduced decidual PR and increased decidual FKBP51 expression (20,31) and that chorioamnionitis and abruption, major etiologies of early PTB, are associated with reduced PR expression (22,24). We now demonstrate that idiopathic and stress-associated PTB, major causes of late PTB, are also triggered by functional P4 withdrawal, albeit mediated through increased FKBP51 expression.…”

“…We previously showed decreased PR and increased FKBP51 expression in the nuclei of decidual cells in placental sections obtained from laboring versus nonlaboring women at term (20,31), suggesting a contributing role for FKBP51 in mediating decidua-specific functional P4 withdrawal during parturition. To investigate if these molecular changes also occur in decidua obtained from iPTB specimens, we assessed FKBP5 and PGR expression by qPCR in decidua basalis specimens obtained from women with iPTB compared with two control groups: 1) negative control-GA-matched women with elective PTB for placenta accreta (PA) or indicated PTB for preeclampsia (PE) or 2) positive control-women in labor at term.…”

“…FKBP52 enhances, whereas FKBP51 attenuates PR-and GR-mediated transcription (25,26). Robust upregulation of FKBP51 levels by ligand-activated GR, and to a lesser extent by ligand-activated PR, is well established (28)(29)(30)(31). Our laboratory recently found (31) that 1) in cultured primary human decidual cells, FKBP51, but not FKBP52 levels, are up-regulated by either dexamethasone, a pure glucocorticoid, or medroxyprogesterone acetate, a mixed progestin-glucocorticoid (32,33), whereas Organon 2058, a pure progestin agonist exerted minimal stimulatory effects; 2) overexpression of FKBP5 resulted in inhibition of PR binding to progesterone response elements (PRE); and 3) at the maternal-fetal interface, FKBP51 is predominantly expressed in decidual cell nuclei with increased expression in term decidual cells among patients in labor compared with nonlaboring controls (31).…”

Evaluation of Progesterone Receptor, FKBP51 and FKBP52, Associated with Uterine Receptivity, in Endometrial Tissue of Women with Repeated Implantation Failure

“…However, based on our researches, no other studies have been conducted for evaluation of FKBP51 gene expression in endometrial tissue of women with gynecological problems to be compared with our study results. Only one study showed that a higher level of FKBP51 gene expression in decidual cells of pregnant women facilitates their labor process by reducing sensitivity of these cells to progesterone, indicating its contribution to progesterone signaling pathway and response of target tissues to progesterone (23).…”

“…In the case of progesterone hormone, FKBP51 and FKBP52 act as progesterone receptor co-chaperons. These immunophilins have a similar structure, but FKBP52 increases the affinity of PR for its ligand while FKBP51 decreases this affinity, thereby reducing the response of target tissue to this hormone (17,(23)(24). Studies showed that Fkbp52 null female mice are infertile due to endometrial receptivity defects, and their inability to sustain pregnancy was related to progesterone hormone resistance (25)(26).…”