慢性应激和肠屏障功能障碍：糖皮质激素受体和转录抑制因子HES1调节紧密连接蛋白Claudin-1启动子。,Scientific Reports

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慢性应激和肠屏障功能障碍：糖皮质激素受体和转录抑制因子HES1调节紧密连接蛋白Claudin-1启动子。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-07-03 , DOI: 10.1038/s41598-017-04755-w
Gen Zheng , Gordon Victor Fon , Walter Meixner , Amy Creekmore , Ye Zong , Michael K. Dame , Justin Colacino , Priya H. Dedhia , Shuangsong Hong , John W. Wiley

慢性应激和糖皮质激素升高与肠道上皮紧密连接蛋白claudin-1（CLDN1）减少有关。人/大鼠CLDN1启动子包含糖皮质激素反应元件（GREs）和邻近的转录阻遏物HES1结合N-box。Notch信号靶HES1表达在隐窝基底部高而糖皮质激素受体（NR3C1）低，并且在隐窝先端反转。慢性应激降低了大鼠结肠结肠HES1和NR3C1的含量，这与CLDN1的下调有关。染色质免疫沉淀实验表明，HES1和NR3C1与大鼠结肠隐窝中的CLDN1启动子结合。NR3C1而不是HES1与CLDN1启动子的结合在慢性应激动物中显着降低，这被NR3C1拮抗剂RU486阻止。我们采用21天的Caco-2 / BBe细胞模型沿隐窝轴复制细胞分化。分化早期的HES1 siRNA治疗会增加CLDN1。相反，在分化后期，皮质醇的应激水平降低了CLDN1，但在早期则没有。HES1高，而NR3C1和CLDN1在早期则较低，而在后期则相反，例如HES1 / NR3C1与CLDN1启动子的结合表现出动态的和相互的模式。这些结果表明，慢性应激通过沿隐窝轴的不同机制损害结肠上皮的稳态和屏障功能。而NR3C1和CLDN1在早期则较低，而在晚期则相反，例如HES1 / NR3C1与CLDN1启动子的结合表现出动态的和相互的模式。这些结果表明，慢性应激通过沿隐窝轴的不同机制损害结肠上皮的稳态和屏障功能。而NR3C1和CLDN1在早期则较低，而在晚期则相反，例如HES1 / NR3C1与CLDN1启动子的结合表现出动态的和相互的模式。这些结果表明，慢性应激通过沿隐窝轴的不同机制损害结肠上皮的稳态和屏障功能。

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Chronic stress and intestinal barrier dysfunction: Glucocorticoid receptor and transcription repressor HES1 regulate tight junction protein Claudin-1 promoter.

Chronic stress and elevated glucocorticoid hormone are associated with decreases in the intestinal epithelial tight junction protein claudin-1 (CLDN1). Human/rat CLDN1 promoters contain glucocorticoid response elements (GREs) and adjacent transcription repressor HES1 binding N-boxes. Notch signaling target HES1 expression was high and glucocorticoid receptor (NR3C1) low at the crypt base and the pattern reversed at the crypt apex. Chronic stress reduced overall rat colon HES1 and NR3C1 that was associated with CLDN1 downregulation. Chromatin-immunoprecipitation experiments showed that HES1 and NR3C1 bind to the CLDN1 promoter in rat colon crypts. The binding of NR3C1 but not HES1 to CLDN1 promoter significantly decreased in chronically stressed animals, which was prevented by the NR3C1 antagonist RU486. We employed the 21-day Caco-2/BBe cell model to replicate cell differentiation along the crypt axis. HES1 siRNA treatment early in differentiation increased CLDN1. In contrast, stress levels of cortisol decreased CLDN1 in late differentiation stage but not in the early stage. HES1 was high, whereas NR3C1 and CLDN1 were low in the early stage which reversed in the late stage, e.g. HES1/NR3C1 binding to CLDN1 promoter demonstrates a dynamic and reciprocal pattern. These results suggest that chronic stress impairs colon epithelium homeostasis and barrier function via different mechanisms along the crypt axis.

更新日期：2017-07-03

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