Estradiol Inhibits Th17 Cell Differentiation through Inhibition of ROR gamma T Transcription by Recruiting the ER alpha/REA Complex to Estrogen Response Elements of the ROR gamma T Promoter

The symptoms of vaginal candidiasis exacerbate in the second half of the menstrual cycle in premenopausal women when the serum estradiol level is elevated. Estradiol has been shown to inhibit Th17 differentiation and production of antifungal IL-17 cytokines. However, little is known about the mechanisms. In the present study, we used mouse splenocytes and found that estradiol inhibited Th17 differentiation through downregulation of Ror gamma t mRNA and protein expression. Estradiol activated estrogen receptor (ER)alpha to recruit repressor of estrogen receptor activity (REA) and form the ER alpha/REA complex. This complex bound to three estrogen response element (ERE) half-sites on the Ror gamma t promoter region to suppress Ror gamma t expression. Estradiol induced Rea mRNA and protein expression in mouse splenocytes. Using Rea small interfering RNA to knock down Rea expression enhanced Ror gamma t expression and Th17 differentiation. Alternatively, histone deacetylase 1 and 2 bound to the three ERE half-sites, independent of estradiol. Histone deacetylase inhibitor MS-275 dose-and time-dependently increased Ror gamma t expression and subsequently enhanced Th17 differentiation. In 15 healthy premenopausal women, high serum estradiol levels are correlated with low ROR gamma T mRNA levels and high REA mRNA levels in the vaginal lavage. These results demonstrate that estradiol upregulates REA expression and recruits REA via ER alpha to the EREs on the ROR gamma T promoter region, thus inhibiting ROR gamma T expression and Th17 differentiation. This study suggests that the estradiol/ER alpha/REA axis may be a feasible target in the management of recurrent vaginal candidiasis.