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-jB. 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.

Leptin Transcriptionally Enhances Peptide Transporter (hPepT1) Expression and Activity via the cAMP-response Element-binding Protein and Cdx2 Transcription Factors

“…Based on our collective findings, we herein propose that the presence of leptin in inflamed colonic mucosa (25) could result to a local high concentration of leptin in contact with colonocytes. Our results suggest that the presence of high leptin concentrations result in increased intracellular cAMP in the colonic epithelial cells, triggering intracellular protein kinase signaling cascades, such as the second messenger system, leading to the subsequent phosphorylation/activation of CREB and Cdx2, which is followed by increased expression of hPepT1 and enhanced uptake of the small di-tri bacterial products that perpetuate intestinal inflammation (21). These findings provide important new insights into intestinal inflammation and may lead to new therapeutic modalities in the future.…”

Intrauterine Growth Restriction Delays Feeding-Induced Gut Adaptation in Term Newborn Pigs

“…That might result in a greater capacity for peptide absorption during the first days of life in IUGR piglets [34] , thereby inducing a high load of antigens that may modulate immune system development [35] . In addition, the elevated expression of PEPT1, which potentially enhanced intestinal transport of bacterial peptides [36] , combined with the higher density of adherent bacteria and translocation, may result in a decrease in barrier function and subsequently may play a role in the IUGR-related modulation of the immune system via the NF-B pathway [37] . The change in the developmental pattern of intestinal IL-6 expression may be an illustration of these phenomena.…”

PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis

“…15,38,39 In addition, we have previously demonstrated that PepT1 is also expressed in immune cells and may transport small proinflammatory peptides such as fMLP, thereby participating in the intestinal inflammatory responses. [20][21][22]48 Importantly, it has recently been shown that a PepT1 polymorphism is associated with IBD. Overall, our studies have revealed that PepT1 may be involved in the pathogenesis of IBD in humans.…”