Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis
Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis
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DOI：
10.1172/jci65842
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发表时间：
2013-09-01
影响因子：
15.9
通讯作者：
Li, Yan Chun
中科院分区：
文献类型：
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作者：
Liu, Weicheng;Chen, Yunzi;Li, Yan Chun
维生素 D 对结肠炎的抑制作用先前已有记载。整体维生素 D 受体 (VDR) 缺失会加剧结肠炎，但上皮和非上皮 VDR 信号传导的相对抗结肠作用尚不清楚。在这里，我们发现克罗恩病或溃疡性结肠炎患者的结肠上皮 VDR 表达显着降低。此外，人VDR（hVDR）在肠上皮细胞（IEC）中的靶向表达可以保护小鼠免受结肠炎的影响。在2,4,6-三硝基苯磺酸、葡聚糖硫酸钠或CD4(+)CD45RB(hi) T细胞移植诱导的实验性结肠炎模型中，IEC表达hVDR的转基因小鼠对结肠炎具有高度抵抗力，与WT小鼠相比，其临床结肠炎评分、结肠组织学损伤和结肠炎症显着降低。用 hVDR 转基因重建 Vdr 缺陷的 IECs 完全使 Vdr 缺失的小鼠免于严重结肠炎和死亡，尽管这些小鼠仍然保持高反应性的 Vdr 缺陷免疫系统。从机制上讲，VDR 信号传导通过阻断 NF-kappa B 激活来减弱 IEC 中的 PUMA 诱导，从而减少 IEC 细胞凋亡。总之，这些结果表明，肠上皮 VDR 信号传导通过保护粘膜上皮屏障来抑制结肠炎，并且这种抗结肠活性独立于非上皮免疫 VDR 作用。
The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4(+)CD45RB(hi) T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-kappa B activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.