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 Rorγt mRNA and protein expression. Estradiol activated estrogen receptor (ER)α to recruit repressor of estrogen receptor activity (REA) and form the ERα/REA complex. This complex bound to three estrogen response element (ERE) half-sites on the Rorγt promoter region to suppress Rorγt expression. Estradiol induced Rea mRNA and protein expression in mouse splenocytes. Using Rea small interfering RNA to knock down Rea expression enhanced Rorγt 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 Rorγt expression and subsequently enhanced Th17 differentiation. In 15 healthy premenopausal women, high serum estradiol levels are correlated with low RORγT mRNA levels and high REA mRNA levels in the vaginal lavage. These results demonstrate that estradiol upregulates REA expression and recruits REA via ERα to the EREs on the RORγT promoter region, thus inhibiting RORγT expression and Th17 differentiation. This study suggests that the estradiol/ERα/REA axis may be a feasible target in the management of recurrent vaginal candidiasis.
Footnotes
This work was supported by National Natural Science Foundation of China Grant 81171512 (to Y.-M. F.) and by Affiliated Hospital of Guangdong Medical College Matching Fund 1100/B010002 (to R.-Y.C.). Z.Y. was partially supported by National Institute of General Medical Sciences Grant P20GM103518 and National Cancer Institute Grant R01CA174714 of the National Institutes of Health, Department of Defense Grants W81XWH-14-1-0050, W81XWH-14-1-0149, and W81XWH-14-1-0458, the Developmental Fund of Tulane Cancer Center, and by Louisiana Cancer Research Consortium funds. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Department of Defense.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- ChIP
- chromatin immunoprecipitation
- Ct
- cycle threshold
- E2
- 17β-estradiol
- ER
- estrogen receptor
- ERE
- estrogen response element
- HDAC
- histone deacetylase
- MAA
- methoxyacetic acid
- qPCR
- quantitative PCR
- qRT-PCR
- real-time quantitative RT-PCR
- REA
- repressor of estrogen receptor activity
- RORα
- retinoid acid receptor–related orphan receptor α
- RORγT
- thymus-specific isoform of retinoid acid receptor–related orphan receptor C
- siRNA
- small interfering RNA
- Treg
- regulatory T cell.
- Received March 28, 2014.
- Accepted February 9, 2015.
- Copyright © 2015 by The American Association of Immunologists, Inc.