Differential regulation of endogenous pro-inflammatory cytokine genes by medroxyprogesterone acetate and norethisterone acetate in cell lines of the female genital tract
Background: Medroxyprogesterone acetate (MPA) and norethisterone (NET) and its derivatives are widely used in female reproductive therapy, but little is known about their mechanisms of action via steroid receptors in the female genital tract. MPA used as a contraceptive has been implicated in effects on local immune function. However, the relative effects of progesterone (Prog), MPA and norethisterone acetate (NET-A) on cytokine gene expression in the female genital tract are unknown. Study Design: Using two epithelial cell lines generated from normal human vaginal (Vk2/E6E7) and ectocervical (Ect1/E6E7) cells as in vitro cell culture model systems for mucosal immunity of the female cervicovaginal environment, we investigated steroid receptor expression and activity as well as regulation of cytokine/chemokine genes by MPA and NET-A, as compared to the endogenous hormone Prog. Results: We show that the Prog, androgen, glucocorticoid and estrogen receptors (PR, AR, GR and ER, respectively) are expressed in both the Vk2/E6E7 and Ect1/E6E7 cell lines, and that the GR and AR are transcriptionally active. This study is the first to show ligand-, promoter- and cell-specific regulation of IL-6, IL-8 and RANTES (regulated-upon-activation, normal T cell expressed and secreted) gene expression by Prog, MPA and NET-A in these cell lines. Moreover, we show that the repression of the TNF-α-induced RANTES gene by MPA in the Ect1/E6E7 cell line is mediated by the AR. Conclusion: Collectively, these data demonstrate that cell lines from different anatomical sites of the female genital tract respond differently to Prog and the synthetic progestins, most likely due to differential actions via different steroid receptors. The results highlight the importance of choice of progestins for immune function in the cervicovaginal environment. They further suggest that choice of progestins in endocrine therapy may have implications for women's risk of susceptibility to infections due to differential actions on genes involved in inflammation and immune function. © 2011 Elsevier Inc.