Colonic miRNA Expression/Secretion, Regulated by Intestinal Epithelial PepT1, Plays an Important Role in Cell-to-Cell Communication during Colitis

Abstract

PepT1 is a member of the proton-oligopeptide cotransporter family SLC15, which mediates the transport of di/tripeptides from intestinal lumen into epithelial cells. MicroRNAs (miRNAs), a small noncoding RNAs (21–23 nucleotides), post-transcriptionally regulate gene expression by binding to the 3′-untranslated regions (UTRs) of their target mRNAs. Although the role of most miRNAs remains elusive, they have been implicated in vital cellular functions such as intestinal epithelial cells differentiation, proliferation, and apoptosis. In the present study, we investigated the effect of intestinal epithelial PepT1 expression on microRNA (miRNA) expression/secretion in the colons of control mice and in mice with experimentally induced colonic inflammation (colitis). The colonic miRNA expression was deregulated in both colitis and control mice but the deregulation of miRNA expression/secretion was specific to colonic tissue and did not affect other tissues such as spleen and liver. Intestinal epithelial PepT1-dependent deregulation of colonic miRNA expression not only affects epithelial cells but also other cell types, such as intestinal macrophages. Importantly, we found the miRNA 23b which was known to be involved in inflammatory bowel disease was secreted and transported between cells to impose a gene-silencing effect on recipient intestinal macrophages. Based on our data, we may conclude that the expression of a specific protein, PepT1, in the intestine affects local miRNA expression/secretion in the colon on a tissue specific manner and may play an important role during the induction and progression of colitis. Colonic miRNA expression/secretion, regulated by intestinal epithelial PepT1, could play a crucial role in cell-to-cell communication during colitis.

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1

“…After intracolonic treatment with the different above mentioned conditions (B), colonic PepT1 expression was determined by Western blotting and immunofluorescent staining (C). Scale bars ϭ 50 m. recent study, overexpression of colonic PepT1 was found to alter the profile of local miRNA expression/secretion in both epithelial and non-epithelial cells such as intestinal macrophages in a tissue-specific manner (35). Our observation of the dysregulated PepT1 in the colon tissues from active IBD patients is consistent with the previous studies of PepT1 involvement in aggravation of intestinal inflammation.…”

PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis

“…The expression of PepT1 regulates the expression/secretion of specific microRNAs (miRNAs), to thereby regulate the expression levels of multiple proteins27. Intestinal miRNA expression is essential for maintaining intestinal homeostasis.…”

Fish c-Jun N-Terminal Kinase (JNK) Pathway Is Involved in Bacterial MDP-Induced Intestinal Inflammation

“…Bacterial MDP has been shown to be transported by intestinal oligopeptide transporter 1 (PepT1) in epithelial cells, which can significantly induce inflammatory responses in animal intestines. Upon the PepT1-mediated transport in intestinal epithelial cells, MDP could be further recognized by the intracellular nucleotide-binding oligomerization domain 2 (NOD2) protein and then by activated receptor-interacting serine/threonineprotein kinase 2 (RIP2) to induce the production of inflammatory cytokines that participate in the intestinal immune response (37,38). Over the past several years, much progress has been made in understanding the immune function of the PepT1-NOD2/RIP2 pathway in bacterial MDP-induced intestinal inflammation in vertebrates (39,40).…”