Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, Georgia 30322, USA.
Gastroenterology. 2011 Oct;141(4):1334-45. doi: 10.1053/j.gastro.2011.06.080. Epub 2011 Jul 14.
BACKGROUND & AIMS: The human di/tripeptide transporter human intestinal H-coupled oligonucleotide 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 also was 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-specific hPepT1 overexpression in villin-hPepT1 transgenic mice increased the severity of inflammation induced by DSS, but not TNBS. Bone marrow transplantation studies showed that hPepT1 expression in intestinal epithelial cells 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-actin-hPepT1 and villin-hPepT1 transgenic mice, indicating that commensal bacteria are required to aggravate intestinal inflammation. Nod2-/-, β-actin-hPepT1 transgenic/Nod2-/-, and villin-hPepT1 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.
人类二肽/三肽转运蛋白人肠道 H 偶联寡核苷酸转运蛋白（hPepT1）在炎症性肠病患者的结肠中异常表达，但其在发病机制中的确切作用尚不清楚。我们研究了 PepT1 对结肠炎小鼠模型中肠道炎症的贡献，以及核苷酸结合寡聚化结构域 2（NOD2）信号通路在结肠上皮 hPepT1 致病活性中的作用。
通过β-肌动蛋白或微管蛋白启动子调节 hPepT1 表达，生成转基因小鼠；使用 2,4,6-三硝基苯磺酸（TNBS）或葡聚糖硫酸钠（DSS）诱导结肠炎，并评估炎症反应。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。
TNBS 和 DSS 在β-肌动蛋白-hPepT1 转基因小鼠中诱导的炎症比野生型同窝仔鼠更严重。微管蛋白-hPepT1 转基因小鼠中肠道上皮细胞特异性 hPepT1 过表达增加了 DSS 诱导的炎症严重程度，但对 TNBS 没有影响。骨髓移植研究表明，肠道上皮细胞和免疫细胞中的 hPepT1 表达在促炎反应中起重要作用。抗生素消除了 hPepT1 过表达对β-肌动蛋白-hPepT1 和微管蛋白-hPepT1 转基因小鼠 DSS 诱导结肠炎中炎症反应的影响，表明共生细菌是加重肠道炎症所必需的。Nod2-/-、β-肌动蛋白-hPepT1 转基因/Nod2-/-和微管蛋白-hPepT1 转基因/Nod2-/-同窝仔鼠对 DSS 诱导的结肠炎的易感性相似，表明 hPepT1 过表达以 NOD2 依赖的方式增加肠道炎症。
PepT1-NOD2 信号通路参与了 DSS 诱导的小鼠结肠炎的加重。
