6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression
6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression
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6-甲酰吲哚(3,2-b)咔唑诱导的芳烃受体激活通过调节claudin-2表达预防肠屏障功能障碍
DOI：
10.1016/j.cbi.2018.04.020
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发表时间：
2018-05-25
影响因子：
5.1
通讯作者：
Yang, Hua
中科院分区：
文献类型：
--
作者：
Ma, Yuanhang;Wang, Qimeng;Yang, Hua
6-甲醛并(3，2-b)咔唑(FICZ)是一种高亲和力的芳香烃受体(AhR)配体，通过激活AhR在炎症性肠病(IBD)中发挥保护作用。白介素6(IL-6)诱导的肠上皮屏障功能障碍参与了IBD的病理过程。本研究探讨FICZ对IL-6诱导的肠上皮屏障损伤的保护作用。我们的数据显示，在葡聚糖硫酸钠(DSS)诱导的结肠炎小鼠模型中，FICZ激活AhR可以减轻结肠炎，减少IL-6和Claudin-2的表达，并维持肠屏障功能。在Caco-2和T84肠上皮细胞中，FICZ还能抑制IL-6诱导的肠上皮通透性增加和claudin-2的表达。小干扰(Si)RNA抑制AhR的表达可逆转FICZ诱导的claudin-2表达下降。此外，IL-6诱导的Claudin-2上调是尾端相关同源盒2(CDX-2)和肝细胞核因子(HNF)-1α增加所必需的。FICZ可抑制IL-6诱导的CDX-2和HNF-1α表达的增加。这些结果揭示了FICZ通过抑制Claudin-2的表达对IL-6所致的肠上皮屏障功能障碍的保护作用。此外，CDX-2和HNF-1α参与了IL-6和FICZ治疗后Claudin-2的调节。因此，与AhR配体相关的化合物可能成为治疗IBD的潜在药物。
6-Formylindolo(3,2-b)carbazole (FICZ), a high-affinity aryl hydrocarbon receptor (AhR) ligand, plays a protective role in inflammatory bowel disease (IBD) through activation of AhR. Interleukin-6 (IL-6) induced intestinal epithelial barrier dysfunction is involved in the pathological process of IBD. In this study, we investigated the protective effects of FICZ on IL-6 induced intestinal epithelial barrier injury. Our data show that AhR activation by FICZ ameliorated colonic inflammation, decreased IL-6 and claudin-2 expression, and maintained intestinal barrier function in a mouse model of dextran sulphate sodium (DSS)-induced colitis. In Caco-2 and T84 intestinal epithelial cells, FICZ also prevented the increase of intestinal epithelial permeability and claudin-2 expression induced by IL-6. Depletion of AhR expression by small interfering (si)RNA reversed FICZ induced decrease of claudin-2. Furthermore, IL-6 induced upregulation of claudin-2 was required for increased caudal-related homeobox 2 (CDX-2) and hepatocyte-nuclear factor (HNF)-1 alpha. However, FICZ repressed the increase of CDX-2 and HNF-1 alpha expression induced by IL-6. These results reveal the protective effects of FICZ on IL-6 induced disruption of intestinal epithelial barrier function through suppressing the expression of claudin-2. In addition, CDX-2 and HNF-1 alpha are involved in the regulation of claudin-2 after IL-6 and FICZ treatment. Therefore compounds related to AhR ligands may be potential pharmaceutical agents to treat IBD.