Estrogen receptor α antagonists mediate changes in CCL20 and CXCL1 secretions in the murine female reproductive tract

PROBLEM Estradiol regulates chemokine secretion from uterine epithelial cells, but little is known about estradiol regulation in vivo or the role of estrogen receptors (ERs). METHOD CCL20 and CXCL1 present in reproductive washes following treatment with selective estrogen receptor modulators (SERMs) were compared with that during estrous and following estradiol-treated ovariectomized BALB/c mice. Cellular regulation was determined using isolated vaginal and uterine epithelial/stromal cells in vitro. RESULTS Uterine and vaginal chemokine secretion is cyclically regulated with CCL20 at low levels but CXCL1 at high levels during high estradiol, generally mimicking estradiol effect in vivo. ERα but not ERβ regulated CCL20/CXCL1 secretion by uterine epithelial cells in vitro and vaginal CCL20 in vivo. Estradiol/SERMs failed to alter uterine CCL20 secretion in ovariectomized mice. Diminished uterine epithelial ERα staining following ovariectomy corresponded with estradiol unresponsiveness of uterine tissue. CONCLUSION Estrogen receptors α regulates CCL20/CXCL1 secretion in the female reproductive tract, and ERα antagonists directly oppose the regulation by estradiol. Understanding ER-mediated antimicrobial chemokine expression is important to elucidate cyclic susceptibility to sexually transmitted pathogens.

New approaches to making the microenvironment of the female reproductive tract hostile to HIV

The studies presented in this review explore three distinct areas with potential for inhibiting HIV infection in women. Based on emerging information from the physiology, endocrinology and immunology of the female reproductive tract (FRT), we propose unique 'works in progress' for protecting women from HIV. Various aspects of FRT immunity are suppressed by estradiol during the menstrual cycle, making women more susceptible to HIV infection. By engineering commensal Lactobacillus to secrete the anti-HIV molecule Elafin as estradiol levels increase, women could be protected from HIV infection. Selective estrogen response modifiers enhance barrier integrity and enhance secretion of protective anti-HIV molecules. Finally, understanding the interactions and regulation of FRT endogenous antimicrobials, proteases, antiproteases, etc., all of which are under hormonal control, will open new avenues to therapeutic manipulation of the FRT mucosal microenvironment. By seeking new alternatives to preventing HIV infection in women, we may finally disrupt the HIV pandemic.