title: Progesterone receptor-A and -B have opposite effects on proinflammatory gene expression in human myometrial cells: implications for progesterone actions in human pregnancy and parturition.
abstract: BACKGROUND
  Progesterone promotes uterine relaxation during pregnancy and its withdrawal induces labor. Progesterone withdrawal in human parturition is mediated in part by changes in the relative levels of the nuclear progesterone receptor isoforms, PR-A and PR-B, in myometrial cells. Parturition also involves myometrial inflammation; however, the functional link between nuclear PR-mediated progesterone actions and inflammation in human myometrial cells is unclear.
  
  
  OBJECTIVE
  Our objective was to determine how PR-A and PR-B regulate progesterone action in human myometrial cells and specifically the expression of genes encoding contraction-associated proteins and proinflammatory mediators.
  
  
  METHODS
  Effects of PR-A and PR-B on the capacity for progesterone to modulate gene expression was determined using an immortalized human myometrial cell line stably transfected with inducible PR-A and PR-B expression transgenes and conditioned to express various PR-A and PR-B levels. Gene expression was assessed by genome wide transcriptome analysis, quantitative RT-PCR and immunoblotting.
  
  
  RESULTS
  PR-A and PR-B were each transcriptionally active in response to progesterone and affected the expression of distinct gene cohorts. The capacity for progesterone to affect gene expression was dependent on the PR-A to PR-B ratio. This was especially apparent for the expression of proinflammatory genes. Progesterone decreased proinflammatory gene expression when the PR-A to PR-B ratio favored PR-B and increased proinflammatory gene expression when the ratio favored PR-A. Progesterone via PR-B increased expression of inhibitor-κBα, a repressor of the nuclear factor-κB transcription factor, and inhibited basal and lipopolysaccharide-induced proinflammatory gene expression. Both of those PR-B-mediated effects were inhibited by PR-A.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Reproductive Biology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland Ohio 44106-5034, USA.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Tan
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yi
authors.forename: Neal S
authors.initials: NS
authors.lastname: Rote
authors.forename: William W
authors.initials: WW
authors.lastname: Hurd
authors.forename: Sam
authors.initials: S
authors.lastname: Mesiano
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D009215:Myometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
chemical_list: D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D011374:Progesterone