The PepT1-NOD2 signaling pathway aggravates induced colitis in mice.
The PepT1-NOD2 signaling pathway aggravates induced colitis in mice.
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DOI：
10.1053/j.gastro.2011.06.080
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发表时间：
2011-10
期刊：
影响因子：
29.4
通讯作者：
Merlin D
中科院分区：
文献类型：
--
作者：
Dalmasso G;Nguyen HT;Ingersoll SA;Ayyadurai S;Laroui H;Charania MA;Yan Y;Sitaraman SV;Merlin D
人类二肽/三肽转运体hPepT1在炎症性肠病患者的结肠中异常表达，尽管其在发病机制中的确切作用尚不清楚。我们研究了小鼠结肠炎模型中PepT1在肠道炎症中的作用，以及核苷酸结合寡聚结构域2 （NOD2）信号通路在结肠上皮hPepT1致病活性中的作用。构建了hPepT1表达受β-actin或villin启动子调控的转基因小鼠；采用2,4,6-三硝基苯磺酸（TNBS）或葡聚糖硫酸钠（DSS）诱导结肠炎，观察炎症反应。我们还研究了NOD2缺失对hPepT1转基因小鼠的影响，以确定PepT1-NOD2信号通路的参与。在β-actin-hPepT1转基因小鼠中，TNBS和DSS诱导的炎症水平比野生型小鼠更严重。在绒毛蛋白-hPepT1转基因小鼠中，肠上皮细胞（IEC）特异性hPepT1过表达增加了DSS诱导的炎症的严重程度，但不增加TNBS。骨髓移植研究表明，hPepT1在IECs和免疫细胞中的表达在促炎反应中具有重要作用。在β-actin - pept1和villin-hPepT1转基因小鼠中，抗生素消除了hPepT1过表达对dss诱导的结肠炎炎症反应的影响，表明加重肠道炎症需要共生菌。Nod2−/−、β-actin-hPepT1转基因/Nod2−/−和villinhPepT1转基因/Nod2−/−的窝鼠对dss诱导的结肠炎的易感性水平相似，表明hPepT1过表达以Nod2依赖的方式增加肠道炎症。PepT1-NOD2信号通路参与dss诱导小鼠结肠炎的加重。
The human di/tripeptide transporter hPepT1 is abnormally expressed in colons of patients with inflammatory bowel disease, although its exact role in pathogenesis is unclear. We investigated the contribution of PepT1 to intestinal inflammation in mouse models of colitis and the involvement of the nucleotide-binding oligomerization domain 2 (NOD2) signaling pathway in the pathogenic activity of colonic epithelial hPepT1. Transgenic mice were generated in which hPepT1 expression was regulated by the β-actin or villin promoters; colitis was induced using 2,4,6-trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulfate (DSS) and the inflammatory responses were assessed. The effects of NOD2 deletion in the hPepT1 transgenic mice was also studied, to determine the involvement of the PepT1–NOD2 signaling pathway. TNBS and DSS induced more severe levels of inflammation in β-actin–hPepT1 transgenic mice than wild-type littermates. Intestinal epithelial cell (IEC)-specific hPepT1 overexpression in villin-hPepT1 transgenic mice increased the severity of inflammation induced by DSS, but not TNBS. Bone marrow transplantation studies demonstrated that hPepT1 expression in IECs and immune cells has an important role in the proinflammatory response. Antibiotics abolished the effect of hPepT1 overexpression on the inflammatory response in DSS-induced colitis in β-actinh–PepT1 and villin-hPepT1 transgenic mice, indicating that commensal bacteria are required to aggravate intestinal inflammation. Nod2−/−, β-actin–hPepT1 transgenic/Nod2−/−, and villinhPepT1 transgenic/Nod2−/− littermates had similar levels of susceptibility to DSS-induced colitis, indicating that hPepT1 overexpression increased intestinal inflammation in a NOD2-dependent manner. The PepT1–NOD2 signaling pathway is involved in aggravation of DSS-induced colitis in mice.
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