title: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida.
authors.forename: Frederick
authors.initials: F
authors.lastname: Schatz
authors.affiliation: Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Guzeloglu-Kayisli
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Murat
authors.initials: M
authors.lastname: Basar
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Lynn F
authors.initials: LF
authors.lastname: Buchwalder
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Nehir
authors.initials: N
authors.lastname: Ocak
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; Department of Histology and Embryology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Guzel
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Seth
authors.initials: S
authors.lastname: Guller
authors.affiliation: Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida.
authors.forename: Nihan
authors.initials: N
authors.lastname: Semerci
authors.affiliation: Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida.
authors.forename: Umit A
authors.initials: UA
authors.lastname: Kayisli
authors.affiliation: Department of Obstetrics and Gynecology, University of South Florida, Morsani College of Medicine, Tampa, Florida. Electronic address: cjlockwood@health.usf.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
mesh_terms: D003656:Decidua / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007743:Labor, Obstetric / Q000187:drug effects*; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D047929:Term Birth / Q000187:drug effects*; D028761:Withholding Treatment; D000099159:Tacrolimus Binding Protein 5
chemical_list: D005938:Glucocorticoids; D011374:Progesterone; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5