MicroRNA-346 mediates tumor necrosis factor α-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases.
MicroRNA-346 mediates tumor necrosis factor α-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases.
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DOI：
10.1097/mib.0000000000000158
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发表时间：
2014-11
影响因子：
4.9
通讯作者：
Li YC
中科院分区：
文献类型：
--
作者：
Chen Y;Du J;Zhang Z;Liu T;Shi Y;Ge X;Li YC
我们最近报道了肠上皮维生素D受体（VDR）信号通过抑制肠上皮细胞凋亡来抑制结肠炎，并且炎症性肠病（IBD）患者结肠上皮VDR水平显著降低。VDR下调促进结肠炎，但IBD中VDR下调的潜在机制尚不清楚。在促炎细胞因子处理下分析结肠癌细胞中的VDR表达。使用结肠癌细胞培养物证实VDR作为miR-346的靶标。在人IBD活检和实验性结肠炎模型中评估炎症、miR-346和VDR之间的关系。我们发现TNF-α抑制VDR表达，同时上调人结肠癌细胞中的miR-346。进一步的研究表明，miR-346通过人VDR转录本3′非翻译区中的特异性靶序列抑制VDR，并且用发夹抑制剂阻断miR-346可消除TNF-α抑制VDR的能力，证实TNF-α通过诱导miR-346下调VDR。因此，在人IBD活检中，上皮VDR的减少与免疫细胞浸润增加和TNF-α和miR-346升高相关。在结肠炎实验模型中，粘膜VDR表达随着结肠炎进展随时间推移而降低，与粘膜中TNF-α和miR-346的诱导呈负相关。这些数据表明，在粘膜炎症期间，TNF-α诱导miR-346，其下调上皮VDR。黏蛋白VDR的减少反过来又损害了粘膜上皮屏障的完整性，进一步推动粘膜炎症和结肠炎的发展。
We recently reported that the gut epithelial vitamin D receptor (VDR) signaling inhibits colitis through inhibition of intestinal epithelial cell apoptosis, and the level of colonic epithelial VDR is markedly reduced in patients with inflammatory bowel diseases (IBD). VDR down-regulation promotes colitis, but the mechanism underlying VDR down-regulation in IBD is unknown. VDR expression was analyzed in colon cancer cells under pro-inflammatory cytokine treatment. VDR as a target of miR-346 was confirmed using colon cancer cell culture. The relationship among inflammation, miR-346 and VDR was assessed in human IBD biopsies and experimental colitis models. We showed that TNF-α suppresses VDR expression while simultaneously up-regulating miR-346 in human colon cancer cells. Further studies demonstrated that miR-346 inhibits VDR by a specific target sequence in the 3′ untranslated region of the human VDR transcript, and blockade of miR-346 with a hairpin inhibitor abrogates the ability of TNF-α to inhibit VDR, confirming that TNF-α down-regulates VDR by inducing miR-346. Consistently, in human IBD biopsies the reduction of epithelial VDR is associated with increased immune cell infiltration and elevation of TNF-α and miR-346. In an experimental model of colitis mucosal VDR expression is reduced over time with the progression of colitis, inversely correlated with the induction of TNF-α and miR-346 in the mucosa. These data suggest that during mucosal inflammation TNF-α induces miR-346, which down-regulates epithelial VDR. Mucosal VDR reduction in turn compromises the integrity of the mucosal epithelial barrier, further driving mucosal inflammation and colitis development.