Estradiol inhibits Th17 cell differentiation through inhibition of ROR?T transcription by recruiting the ER?/REA complex to estrogen response elements of the ROR?T promoter.

ABSTRACT: 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?t mRNA and protein expression. Estradiol activated estrogen receptor (ER)? to recruit repressor of estrogen receptor activity (REA) and form the ER?/REA complex. This complex bound to three estrogen response element (ERE) half-sites on the Ror?t promoter region to suppress Ror?t expression. Estradiol induced Rea mRNA and protein expression in mouse splenocytes. Using Rea small interfering RNA to knock down Rea expression enhanced Ror?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?t expression and subsequently enhanced Th17 differentiation. In 15 healthy premenopausal women, high serum estradiol levels are correlated with low ROR?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? to the EREs on the ROR?T promoter region, thus inhibiting ROR?T expression and Th17 differentiation. This study suggests that the estradiol/ER?/REA axis may be a feasible target in the management of recurrent vaginal candidiasis.

SUBMITTER: Chen RY 

PROVIDER: S-EPMC4390502 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature