Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response
Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response
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DOI：
10.3389/fimmu.2017.00661
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发表时间：
2017-06-07
影响因子：
7.3
通讯作者：
Wang, Guoshun
中科院分区：
文献类型：
--
作者：
Ng, Hang Pong;Jennings, Scott;Wang, Guoshun
急性酒精暴露抑制细胞炎症反应。根本机制尚未完全确定。在这里，我们报告说，酒精能够激活糖皮质激素受体（GR）信号在糖皮质激素（GC）和上调糖皮质激素诱导的亮氨酸拉链（gilz），一个突出的GC反应基因的情况下。这种非典型的GR激活并不被米非司酮（一种有效的GC竞争剂）阻断。Gilz的近端启动子，包括五个GC响应元件（GRES），被纳入并在荧光素酶报告系统中进行测试。GRES的缺失和/或突变废除了启动子对酒精的响应。因此，GR-GRE相互作用转导了酒精对gilz的作用。酒精诱导GR核转位，这是由酒精脱氢酶抑制剂fomepizole增强，这表明它是酒精，而不是其代谢产物，产生的效果。凝胶迁移率变动分析表明，unliganded GR能够结合GRES，这种相互作用经受住了临床相关水平的酒精。通过CRISPR/Cas9基因靶向的GR敲除或通过小RNA干扰的GILZ消耗减少了对LPS的细胞炎症反应的酒精抑制。因此，一个以前未认识到的，非经典的GR激活gilz参与酒精调节细胞免疫反应。
Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gilz), a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs), was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR-GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response.