Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter.
Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter.
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DOI：
10.4049/jimmunol.1400806
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发表时间：
2015-04-15
期刊：
影响因子：
--
通讯作者：
You Z
中科院分区：
文献类型：
--
作者：
Chen RY;Fan YM;Zhang Q;Liu S;Li Q;Ke GL;Li C;You Z
在绝经前妇女月经周期的后半段，当血清雌二醇水平升高时，阴道念珠菌病的症状加重。已经显示，依匹林抑制Th17分化和抗真菌白细胞介素-17（IL-17）细胞因子的产生。然而，对机制知之甚少。在本研究中，我们使用小鼠脾细胞，发现雌二醇通过下调Ror γ t mRNA和蛋白表达来抑制Th17分化。雌激素可激活ER α募集雌激素受体活性抑制因子（REA），形成ER α/REA复合物。该复合物与Ror γ t启动子区的3个雌激素反应元件（ERE）半位点结合，抑制Ror γ t的表达。Escherichia coli诱导小鼠脾细胞Rea mRNA和蛋白表达。使用Rea siRNA敲低Rea表达增强Ror γ t表达和Th17分化。另一方面，组蛋白去乙酰化酶（HDAC）1和2绑定到三个ERE半位点，独立于雌二醇。HDAC抑制剂MS-275剂量和时间依赖性地增加Ror γ t表达，随后增强Th17分化。在15名健康绝经前妇女中，高血清雌二醇水平与阴道灌洗液中低ROR γ T mRNA水平和高REA mRNA水平相关。这些结果表明，雌二醇上调REA的表达，并通过ER α将REA募集到ROR γ T启动子区域的ERE，从而抑制ROR γ T表达和Th17分化。本研究提示雌二醇-ER α-REA轴可能是治疗复发性阴道念珠菌病的一个可行的靶点。
The symptoms of vaginal candidiasis exacerbate in the second half of the menstrual cycle in the premenopausal women when the serum estradiol level is elevated. Estradiol has been shown to inhibit Th17 differentiation and production of antifungal interleukin-17 (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 down-regulation of Rorγt mRNA and protein expression. Estradiol activated ERα to recruit repressor of estrogen receptor activity (REA) and form 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 siRNA to knockdown Rea expression enhanced Rorγt expression and Th17 differentiation. On the other hand, histone deacetylase (HDAC) 1 and 2 bound to the three ERE half-sites, independent of estradiol. HDAC 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 up-regulates 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.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
30.5
作者：
Acosta-Rodriguez, Eva V.;Napolitani, Giorgio;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.1152/ajplung.00344.2007
发表时间：
2009-02-01
影响因子：
4.9
作者：
Kreindler, James L.;Bertrand, Carol A.;Kolls, Jay K.
通讯作者：
Kolls, Jay K.
影响因子：
4.8
作者：
Kurtev, V;Margueron, R;Seiser, C
通讯作者：
Seiser, C