PepT1 介导的三肽 KPV 摄取可减少肠道炎症。,Gastroenterology

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PepT1 介导的三肽 KPV 摄取可减少肠道炎症。
Gastroenterology ( IF 25.7 ) Pub Date : 2007-10-17 , DOI: 10.1053/j.gastro.2007.10.026
Guillaume Dalmasso ₁ , Laetitia Charrier-Hisamuddin , Hang Thi Thu Nguyen , Yutao Yan , Shanthi Sitaraman , Didier Merlin

Affiliation

背景与目的 KPV 是一种三肽 (Lys-Pro-Val)，具有抗炎特性；然而，其作用机制仍然未知。PepT1 是一种二/三肽转运蛋白，通常在小肠中表达，并在炎症性肠病 (IBD) 期间在结肠中诱导。本研究的目的是 1) 研究 KPV 抗炎作用是否在肠上皮细胞和免疫细胞中是 PepT1 介导的，2) 检查两种小鼠结肠炎模型的抗炎作用。方法在存在或不存在 KPV 的情况下，用促炎细胞因子刺激人肠上皮细胞 Caco2-BBE、HT29-Cl.19A 和人 T 细胞 (Jurkat)。使用 NF-κB 荧光素酶基因报告基因、蛋白质印迹、实时 RT-PCR 和 ELISA 评估 KPV 抗炎作用。吸收实验是使用冷 KPV 作为 PepT1 放射性标记底物的竞争者或使用 [(3) H] KPV 来确定 KPV 吸收的动力学特征进行的。还在 DSS 和 TNBS 诱导的小鼠结肠炎中研究了 KPV 的抗炎作用。将 KPV 添加到饮用水中，并通过组织学水平和促炎细胞因子 mRNA 表达评估炎症。结果纳摩尔浓度的 KPV 抑制 NF-κB 和 MAP 激酶炎症信号通路的激活，并减少促炎细胞因子的分泌。我们发现 KPV 通过在免疫和肠上皮细胞中表达的 PepT1 起作用。此外，口服 KPV 可降低 DSS 和 TNBS 诱导的结肠炎的发生率，这表明促炎细胞因子表达的减少。

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PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation.

BACKGROUND & AIMS KPV is a tripeptide (Lys-Pro-Val), which possesses anti-inflammatory properties; however, its mechanisms of action still remain unknown. PepT1 is a di/tripeptide transporter normally expressed in the small intestine and induced in colon during inflammatory bowel disease (IBD). The aim of this study was to 1) investigate whether the KPV anti-inflammatory effect is PepT1-mediated in intestinal epithelian and immune cells, and 2) examine the anti-inflammatory effects in two models of mice colitis. METHODS Human intestinal epithelial cells Caco2-BBE, HT29-Cl.19A, and human T cells (Jurkat) were stimulated with pro-inflammatory cytokines in the present or absence of KPV. KPV anti-inflammatory effect was assessed using a NF-kappaB luciferase gene reporter, Western blot, real-time RT-PCR and ELISA. Uptake experiments were performed using cold KPV as a competitor for PepT1 radiolabelled substrate or using [(3)H]KPV to determine kinetic characteristics of KPV uptake. Anti-inflammatory effect of KPV was also investigated in DSS- and TNBS-induced colitis in mice. KPV was added to drinking water and inflammation was assessed at the histologic level and by proinflammatory cytokine mRNA expression. RESULTS Nanomolar concentrations of KPV inhibit the activation of NF-kappaB and MAP kinase inflammatory signaling pathways, and reduce pro-inflammatory cytokine secretion. We found that KPV acts via PepT1 expressed in immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of DSS- and TNBS-induced colitis indicated by a decrease in pro-inflammatory cytokine expression. CONCLUSIONS This study indicates tht KPV is transported into cells by PepT1 and might be a new therapeutic agent for IBD.

更新日期：2019-11-01

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