title: Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT 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 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.
authors.affiliation: Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China; Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and.
authors.forename: Rong-Yi
authors.initials: RY
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China; zyou@tulane.edu ymfan1963@163.com.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Fan
authors.affiliation: Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
authors.forename: Qingli
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China;
authors.forename: Guo-Lin
authors.initials: GL
authors.lastname: Ke
authors.affiliation: Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China;
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and Department of Orthopaedic Surgery, Tulane University Health Sciences Center, New Orleans, LA 70112; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, LA 70112; Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA 70112; and Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112 zyou@tulane.edu ymfan1963@163.com.
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002177:Candidiasis / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000276:immunology*; D047628:Estrogen Receptor alpha / Q000276:immunology*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology*; D000091402:Prohibitins; D011725:Pyridines / Q000494:pharmacology; D012097:Repressor Proteins / Q000276:immunology*; D020218:Response Elements / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014621:Vagina / Q000276:immunology / Q000473:pathology
chemical_list: D001549:Benzamides; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D046912:Multiprotein Complexes; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C000717331:PHB2 protein, human; D000091402:Prohibitins; D011725:Pyridines; C539900:RORC protein, human; D012097:Repressor Proteins; C118739:entinostat; D004958:Estradiol