title: Negative effects of progesterone receptor isoform-A on human placental activity of the noncanonical NF-κB signaling.
abstract: BACKGROUND
  Progesterone (P4)contributes to the maintenance of human pregnancy, in part by inhibiting activity of the human pro-labor genes CRH and cyclooxygenase-2 (COX-2). However, the molecular mechanisms underlying the action of P4 remain poorly defined. We have shown that in human placenta, the constitutively activated noncanonical nuclear factor (NF)-κB pathway positively regulates CRH and COX-2, which is further stimulated by glucocorticoid receptor signaling.
  
  
  OBJECTIVE
  We investigated the role of P4 receptor (PR) in the regulation of nuclear activity of v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)/NF-κB2 and, in turn, expression of placental CRH and COX-2.
  
  
  METHODS
  We used a variety of techniques including gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, quantitative RT-PCR, and immunohistochemical staining assays in human placental tissues and primary culture of human cytotrophoblast.
  
  
  RESULTS
  We identified PR isoform-A (PR-A) as the only isoform of PR produced in human placenta. PR-A levels were lower in term placenta than in midterm placenta. Depletion of PR-A by short interfering RNA derepressed inhibition of CRH and COX-2 by P4 and the synthetic progestin 17α-hydroxyprogesterone caproate. Overexpression of PR-A inhibited transcription of CRH and COX-2, which was further downregulated by treatment with P4 or 17α-hydroxyprogesterone caproate. Such an inhibition was mediated by a negative functional interaction of PR-A with the activity of RelB/NF-κB2.
  
  
  CONCLUSIONS
  P4 inhibits the pro-labor genes CRH and COX-2 via PR-A repression of the noncanonical NF-κB signaling in human placenta. Characterization of these pathways may identify potential drug targets for prevention of preterm birth.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences (B.W., N.P., M.R., T.R.), Division of Maternal-Fetal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901; and Department of Obstetrics, Gynecology, and Women's Health (N.R.), Rutgers New Jersey Medical School, Newark, New Jersey 07101.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Wang
authors.forename: Nataliya
authors.initials: N
authors.lastname: Parobchak
authors.forename: Max
authors.initials: M
authors.lastname: Rosen
authors.forename: Natalie
authors.initials: N
authors.lastname: Roche
authors.forename: Todd
authors.initials: T
authors.lastname: Rosen
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D006908:Hydroxyprogesterones / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006908:Hydroxyprogesterones; D016328:NF-kappa B; D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; D000077713:17 alpha-Hydroxyprogesterone Caproate; D011374:Progesterone; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human