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Estradiol Inhibits Th17 Cell Differentiation through Inhibition of RORγT Transcription by Recruiting the ERα/REA Complex to Estrogen Response Elements of the RORγT Promoter

Rong-Yi Chen, Yi-Ming Fan, Qiuyang Zhang, Sen Liu, Qingli Li, Guo-Lin Ke, Chen Li and Zongbing You
J Immunol April 15, 2015, 194 (8) 4019-4028; DOI: https://doi.org/10.4049/jimmunol.1400806
Rong-Yi Chen
*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
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Yi-Ming Fan
*Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China;
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Qiuyang Zhang
†Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and
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Sen Liu
†Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and
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Qingli Li
†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;
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Guo-Lin Ke
*Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China;
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Chen Li
*Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China;
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Zongbing You
†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
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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.
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The Journal of Immunology: 194 (8)
The Journal of Immunology
Vol. 194, Issue 8
15 Apr 2015
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Estradiol Inhibits Th17 Cell Differentiation through Inhibition of RORγT Transcription by Recruiting the ERα/REA Complex to Estrogen Response Elements of the RORγT Promoter
Rong-Yi Chen, Yi-Ming Fan, Qiuyang Zhang, Sen Liu, Qingli Li, Guo-Lin Ke, Chen Li, Zongbing You
The Journal of Immunology April 15, 2015, 194 (8) 4019-4028; DOI: 10.4049/jimmunol.1400806

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Estradiol Inhibits Th17 Cell Differentiation through Inhibition of RORγT Transcription by Recruiting the ERα/REA Complex to Estrogen Response Elements of the RORγT Promoter
Rong-Yi Chen, Yi-Ming Fan, Qiuyang Zhang, Sen Liu, Qingli Li, Guo-Lin Ke, Chen Li, Zongbing You
The Journal of Immunology April 15, 2015, 194 (8) 4019-4028; DOI: 10.4049/jimmunol.1400806
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