Medroxyprogesterone acetate differentially regulates interleukin (IL) -12 and IL-10 in a human ectocervical epithelial cell line in a glucocorticoid receptor (GR) -dependent manner
Louw-du Toit, R.; Hapgood, J.P.; Africander, D.
Journal of Biological Chemistry 289(45): 31136-31149
2014
ISSN/ISBN: 1083-351X PMID: 25202013 DOI: 10.1074/jbc.m114.587311Document Number: 624868
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.