Medroxyprogesterone acetate differentially regulates interleukin (IL)-12 and IL-10 in a human ectocervical epithelial cell line in a glucocorticoid receptor (GR)-dependent manner [Signal Transduction]

September 8th, 2014 by Louw-du Toit, R., Hapgood, J. P., Africander, D.

Medroxyprogesterone acetate (MPA), designed to mimic the actions of the endogenous hormone progesterone (Prog), is extensively used by women as a contraceptive and in hormone replacement therapy (HRT). 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 vs. Prog, in an in vitro cell culture model of the female ectocervical environment. This study shows that Prog and MPA significantly increase the expression of the IL-12p40 and IL-12p35 genes, while 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 Prog- and MPA-bound GR to the IL-12p40 promoter requires CCAAT enhancer binding protein (C/EBP)-β and nuclear factor kappa B (NFκB), while recruitment to the IL-10 promoter requires signal transducer and activator of transcription (STAT)-3. These results suggest that both Prog and MPA may modulate inflammation in the ectocervix via this genomic mechanism.
  • Posted in Journal of Biological Chemistry, Publications
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