Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice
Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice
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DOI：
10.1172/jci96636
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发表时间：
2018-08-01
影响因子：
15.9
通讯作者：
Libert, Claude
中科院分区：
文献类型：
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作者：
Ballegeer, Marlies;Van Looveren, Kelly;Libert, Claude
TNF是许多炎性疾病的重要介质，例如，炎症性肠病（IBD）。在IBD中，TNF产生的急性增加可导致疾病发作。糖皮质激素（GC）是结合并激活糖皮质激素受体（GR）的类固醇，能够保护动物和人类免受急性TNF诱导的炎症症状。在TNF诱导的致死性炎症模型中研究了GR二聚体依赖性靶基因转录反应较差的小鼠。与GRWT/WT小鼠相反，这些GRdim/dim小鼠显示TNF敏感性的显著增加和GC地塞米松（DEX）保护的缺乏。未受攻击的GRdim/dim小鼠具有强烈的IFN刺激基因（ISG）特征，沿着STAT 1上调和磷酸化。这种ISG特征是肠道特异性的，并且基于我们对抗生素的研究，取决于肠道微生物群。GR二聚体直接与STAT 1启动子中的短DNA序列结合，称为反向重复负GRE（IR-nGRE）元件。GRdim/dim小鼠中STAT 1控制不良导致无法抑制ISG基因，导致TNF过度诱导坏死性凋亡。我们的研究结果支持肠道微生物群，IFN，坏死性凋亡和GR在对急性炎症挑战的基础反应和GC的药理学干预中的关键相互作用。
TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs.