title: Medroxyprogesterone acetate differentially regulates interleukin (IL)-12 and IL-10 in a human ectocervical epithelial cell line in a glucocorticoid receptor (GR)-dependent manner.
abstract: Medroxyprogesterone acetate (MPA), designed to mimic the actions of the endogenous hormone progesterone (P4), is extensively used by women as a contraceptive and in hormone replacement therapy. However, little is known about the steroid receptor-mediated molecular mechanisms of action of MPA in the female genital tract. In this study, we investigated the regulation of the pro-inflammatory cytokine, interleukin (IL)-12, and the anti-inflammatory cytokine IL-10, by MPA versus P4, in an in vitro cell culture model of the female ectocervical environment. This study shows that P4 and MPA significantly increase the expression of the IL-12p40 and IL-12p35 genes, whereas IL-10 gene expression is suppressed in a dose-dependent manner. Moreover, these effects were abrogated when reducing the glucocorticoid receptor (GR) levels with siRNA. Using a combination of chromatin immunoprecipitation (ChIP), siRNA, and re-ChIP assays, we show that recruitment of the P4- and MPA-bound GR to the IL-12p40 promoter requires CCAAT enhancer-binding protein (C/EBP)-β and nuclear factor κB (NFκB), although recruitment to the IL-10 promoter requires signal transducer and activator of transcription (STAT)-3. These results suggest that both P4 and MPA may modulate inflammation in the ectocervix via this genomic mechanism.
authors.affiliation: From the Department of Biochemistry, University of Stellenbosch, Private Bag X1, Matieland 7602 and.
authors.forename: Renate
authors.initials: R
authors.lastname: Louw-du Toit
authors.affiliation: the Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7700, South Africa.
authors.forename: Janet P
authors.initials: JP
authors.lastname: Hapgood
authors.affiliation: From the Department of Biochemistry, University of Stellenbosch, Private Bag X1, Matieland 7602 and drho@sun.ac.za.
authors.forename: Donita
authors.initials: D
authors.lastname: Africander
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D002584:Cervix Uteri / Q000378:metabolism; D003271:Contraceptive Agents, Female / Q000737:chemistry; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation; D023281:Genomics; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35 / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism*; D017258:Medroxyprogesterone Acetate / Q000737:chemistry*; D016328:NF-kappa B / Q000378:metabolism; D011372:Progestins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D003271:Contraceptive Agents, Female; C508609:IL10 protein, human; C508858:IL12A protein, human; C500879:IL12B protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; D011372:Progestins; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D017258:Medroxyprogesterone Acetate
keywords: Cervical Epithelium; Contraception; Cytokines; Gene Regulation; Glucocorticoid; Glucocorticoid Receptor; Inflammation; Medroxyprogesterone Acetate; Progesterone; Progestin