title: Differential effects of progesterone on COX-2 and Mn-SOD expressions are associated with histone acetylation status of the promoter region in human endometrial stromal cells.
abstract: BACKGROUND
  Progesterone differently regulates TNFα-induced gene expression of cyclooxygenase-2 (COX-2) and manganese superoxide dismutase (Mn-SOD) in human endometrial stromal cells (ESC).
  
  
  OBJECTIVE
  The present study investigated the mechanisms by which TNFα and progesterone affect the expressions of COX-2 and Mn-SOD in ESC.
  
  
  METHODS
  ESC were incubated with TNFα and progesterone. COX-2 and Mn-SOD mRNA expression was determined by real-time RT-PCR. Nuclear factor (NF)-κB binding to the promoter region or histone acetylation status of the NF-κB response element was analyzed by a chromatin immunoprecipitation assay.
  
  
  RESULTS
  TNFα increased COX-2 and Mn-SOD mRNA levels. Progesterone (10(-6) M) suppressed TNFα-induced COX-2 mRNA expression, whereas TNFα-induced Mn-SOD expression was not inhibited by progesterone. The inhibitory effect of progesterone was abolished by knockdown of progesterone receptors by small interfering RNA. Chromatin immunoprecipitation assay revealed that TNFα increased NF-κB binding at both the COX-2 promoter and the Mn-SOD enhancer and that progesterone inhibited only the NF-κB binding at the COX-2 promoter. The histone acetylation level of the NF-κB response element of the Mn-SOD enhancer was lower than that of the COX-2 promoter. However, when histone acetylation was induced by histone deacetylase inhibitors, progesterone inhibited the TNFα-induced NF-κB binding to the Mn-SOD enhancer.
  
  
  CONCLUSIONS
  TNFα increased COX-2 and Mn-SOD expression via NF-κB activation. Progesterone inhibited COX-2 expression by inhibiting the binding of NF-κB to its response element but did not inhibit TNFα-induced Mn-SOD expression. The gene-specific action of progesterone may be due to the difference in chromatin structure at the NF-κB response elements in the COX-2 promoter and Mn-SOD enhancer.
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tamura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Taketani
authors.forename: Lifa
authors.initials: L
authors.lastname: Lee
authors.forename: Fumie
authors.initials: F
authors.lastname: Kizuka
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Ryo
authors.initials: R
authors.lastname: Maekawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Asada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamura
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sugino
mesh_terms: D000107:Acetylation; D000328:Adult; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D006657:Histones; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase