INTRODUCTION

One of the normal transport functions of gut epithelial cells is the absorption of small peptides from the diet by peptide transport activity (1). This is mediated via the H⁺-coupled oligopeptide transporter (PepT1) which is located at the apical membrane of intestinal epithelial cells (IEC) and which cotransports peptides and H⁺ (2). The specificity of hPepT1 is broad and includes many di- and tripeptides in addition to various peptide-derived drugs (3–8). PepT1 is mainly expressed in brush-border membranes of enterocytes in the small intestine, in proximal tubular cells of the S1 segment of the kidney, and in bile-duct epithelial cells (4, 5, 9–15). By contrast, in the colon, expression of PepT1 mRNA and protein is low (16) and sometimes cannot be detected (10, 15, 17). Although human PepT1 is not expressed in normal colonic epithelial cells (10, 16, 17), we detected its expression at the apical membrane of epithelial cells in chronically inflamed colon (17). Interestingly, we have also shown that immune cells, such as macrophages, which are in close contact with the lamina propria of the intestine, also express PepT1 at their membranes (17, 18).

Since expression of colonic hPepT1 is up-regulated in IBD, its transport activity constitutes a potential new target for anti-inflammatory therapies. Furthermore, the importance of hPepT1 expression by immune cells during intestinal inflammation should be evaluated as it may be therapeutically advantageous to develop PepT1-mediated anti-inflammatory drugs. The tripeptide KPV (Lys-Pro-Val), which is the C-terminal sequence of α-melanocyte stimulating hormone (α-MSH), has anti-inflammatory activity (19–21) and, although the underlying mechanisms remain to be determined, it is known that KPV inhibits NF-κB activation, indicating inhibition of pro-inflammatory cytokine synthesis. In the present study, we examine the tripeptide KPV as a mediator of anti-inflammatory effects via PepT1 expressed in inflamed colonic epithelial and immune cells as well as its anti-inflammatory properties in vivo using murine models of colitis.