PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation

Gastroenterology. 2008 Jan;134(1):166-78. doi: 10.1053/j.gastro.2007.10.026. Epub 2007 Oct 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Chemokines / metabolism
  • Colitis / metabolism*
  • Colitis / pathology
  • Colitis / prevention & control*
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Female
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Melanocyte-Stimulating Hormones / pharmacokinetics*
  • Melanocyte-Stimulating Hormones / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / pharmacokinetics*
  • Peptide Fragments / therapeutic use*
  • Peptide Transporter 1
  • Symporters / metabolism*


  • Chemokines
  • Peptide Fragments
  • Peptide Transporter 1
  • Slc15a1 protein, mouse
  • Symporters
  • MSH (11-13)
  • Melanocyte-Stimulating Hormones