The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor

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dc.contributor.authorGovender, Yashinien_ZA
dc.contributor.authorAvenant, Chanelen_ZA
dc.contributor.authorVerhoog, Nicolette J. D.en_ZA
dc.contributor.authorRay, Roslyn M.en_ZA
dc.contributor.authorGrantham, Nicholas J.en_ZA
dc.contributor.authorAfricander, Donitaen_ZA
dc.contributor.authorHapgood, Janet P.en_ZA
dc.date.accessioned2016-03-01T06:00:47Z
dc.date.available2016-03-01T06:00:47Z
dc.date.issued2014-05-19
dc.descriptionPlease cite as follows: Govender, Y. et al. 2014. The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor. PLoS ONE, 9(5):e96497, doi:10.1371/journal.pone.0096497.en_ZA
dc.descriptionThe original publication is available at http://journals.plos.orgen_ZA
dc.description.abstractClinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4–20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.en_ZA
dc.description.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096497
dc.description.versionPublisher's versionen_ZA
dc.format.extent17 pagesen_ZA
dc.identifier.citationGovender, Y. et al. 2014. The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptor. PLoS ONE, 9(5):e96497, doi:10.1371/journal.pone.0096497.en_ZA
dc.identifier.issn1932-6203 (online)
dc.identifier.otherdoi:10.1371/journal.pone.0096497
dc.identifier.urihttp://hdl.handle.net/10019.1/98234
dc.language.isoen_ZAen_ZA
dc.publisherPLoSen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectMedroxyprogesterone acetateen_ZA
dc.subjectContraceptive drugs, Injectableen_ZA
dc.subjectAnti-inflammatory agentsen_ZA
dc.subjectGlucocorticoids -- Receptorsen_ZA
dc.titleThe injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in endocervical cells via the glucocorticoid receptoren_ZA
dc.typeArticleen_ZA
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