Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1 activation in colonic epithelial cells
Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1 activation in colonic epithelial cells
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DOI：
10.1152/ajpgi.00061.2021
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发表时间：
2021-05-01
影响因子：
4.5
通讯作者：
Du, Jie
中科院分区：
文献类型：
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作者：
Xue, Gang;Gao, Ruifang;Du, Jie
据报道，维生素 D/维生素 D 受体 (VDR) 信号传导对炎症性肠病 (IBD) 的发病或进展具有保护作用，缺氧诱导因子 1a (HIF-1a) 激活被证明与化学诱导的结肠炎密切相关。然而，维生素 D/VDR 信号传导和 HIF-1a 在 IBD 发展中的关联仍然是个谜。在这里，我们发现溃疡性结肠炎 (UC) 患者病变组织的结肠上皮细胞中 HIF-1a 表达大幅增加。一致地，在 TNFa 处理后，结肠上皮细胞中 HIF-1a 的激活也以 NF-KB 通路依赖性方式得到改善。在动物模型中，HIF-1a 抑制剂治疗可改善 2,4,6-三硝基苯磺酸 (TNBS) 或硫酸葡聚糖钠 (DSS) 诱导的结肠炎。在细胞或结肠炎动物模型中，维生素 D/VDR 信号通过调节 NF-KB 通路抑制结肠上皮细胞中 HIF1a 的过度表达，从而抑制这些细胞中 IFNc 和 IL-1b 的过度产生。总的来说，这些数据表明维生素 D/VDR 信号传导至少部分通过抑制结肠上皮细胞中的 HIF-1a 表达来缓解动物模型中结肠炎的发展。新颖且值得注意的这项研究表明，维生素 D/VDR 信号通过抑制结肠上皮细胞中 HIF-1a 的激活来抑制结肠炎。由于维生素 D/VDR 信号传导的作用仅对似乎缺乏维生素 D 的患者明显，因此需要证明补充维生素 D 对不缺乏维生素 D 的患者的益处。
Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD), and hypoxia-inducible factor 1a (HIF-1a) activation is demonstrated to be closely associated with chemicalinduced colitis. However, the association between vitamin D/VDR signaling and HIF-1a on IBD development remains a mystery. Here, we showed that HIF-1a expression was largely increased in the colonic epithelial cells of diseased tissues from patients with ulcerative colitis (UC). Consistently, HIF-1a activation was also improved in colonic epithelial cells upon TNFa treatment in a NF-KB pathway-dependent manner. HIF-1a inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF1a overexpression in colonic epithelial cells via regulating NF-KB pathway, resulting in the inhibition of IFNc and IL-1b overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1a expression in colonic epithelial cells. NEW & NOTEWORTHY This study demonstrates vitamin D/VDR signaling inhibits colitis by suppressing HIF-1a activation in colonic epithelial cells. Since the effect of vitamin D/VDR signaling is only apparent on patients who seem to be vitamin D deficient, the benefits of vitamin D supplementation in patients who are not vitamin D deficient need to be proven.