The oligopeptide transporter hPepT1: gateway to the innate immune response

Abstract

Bacterial products that are normally present in the lumen of the colon, such as N-formylated peptides and muramyl-dipeptide, are important for inducing the development of mucosal inflammation. The intestinal dipeptide transporter, hPepT1, which is expressed in inflamed but not in noninflamed colonic epithelial cells, mediates the transport of these bacterial products into the cytosol of colonic epithelial cells. The small bacterial peptides subsequently induce an inflammatory response, including the induction of MHC class I molecules expression and cytokines secretion, via the activation of nucleotide-binding site and leucine-rich repeat (NBS-LRR) proteins, for example NOD2, and activation of NF-kappaB. Subsequent secretion of chemoattractants by colonic epithelial cells induces the movement of neutrophils through the underlying matrix, as well as across the epithelium. These bacterial products can also reach the lamina propria through the paracellular pathway and across the basolateral membrane of epithelial cells. As a consequence, small formylated peptides can interact directly with immune cells through specific membrane receptors. Since immune cells, including macrophages, also express hPepT1, they can transport small bacterial peptides into the cytosol where these may interact with the NBS-LRR family of intracellular receptors. As in intestinal epithelial cells, the presence of these small bacterial peptides in immune cells may trigger immune response activation.