title: Cyclic AMP enhances progesterone action in human myometrial cells.
abstract: Cyclic AMP (cAMP) has been shown to promote progesterone and glucocorticoid action in a variety of cellular settings. In this study, we have used human myometrial cells to investigate whether cAMP potentiates the ability of progesterone to repress IL-1β-driven COX-2 expression. We found that forskolin enhanced progesterone-repression of IL-1β-driven COX-2 expression in association with delayed IL-1β-induced nuclear phospho-p65 entry and reduced NF-κB binding to the COX-2 promoter. Further, forskolin enhanced the progesterone-induced expression of FKBP5 and 11βHSD1, progesterone-driven activity of a progesterone response element (PRE) and progesterone receptor (PR)-B binding to a transfected PRE. In addition, forskolin treatment increased PR-B levels and reduced the PR-A:PR-B ratio while acutely decreasing the association between PR and nuclear receptor co-repressor (NCoR) and reducing NCoR levels after 6h. These findings are of importance in situations where enhancing progesterone activity is desirable, for example in the management of endometrial cancer, the promotion of endometrial receptivity or the maintenance of myometrial quiescence during pregnancy.
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK; Department of Obstetrics and Gynecology, Third Military Medical University Southwest Hospital, Chongqing 400038, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Lei
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Johann
authors.initials: J
authors.lastname: Malawana
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Yulia
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Suren R
authors.initials: SR
authors.lastname: Sooranna
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Department of Obstetrics and Gynecology, Third Military Medical University Southwest Hospital, Chongqing 400038, PR China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, The University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Grammatopoulos
authors.affiliation: Imperial College Parturition Research Group, Academic Department of Obstetrics & Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Electronic address: mark.johnson@imperial.ac.uk.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Johnson
mesh_terms: D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D009215:Myometrium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D005576:Colforsin; D011374:Progesterone; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Cyclo-oxygenase-2; Human myometrial cells; NCoR; PR; PRE; Progesterone; SMRT; cAMP; cyclic AMP; nuclear receptor co-repressor; progesterone receptor; progesterone response element; silencing mediator for retinoid and thyroid hormone receptor