Background: The organic cation transporter OCTN2 is located on the IBD5 risk allele and has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). It expressed in the apical membrane of gut epithelium and transports many solutes including bacteria-derived mediators which appear to be involved in host-microbial interactions. To explore its role further, we examined its expression and potential regulatory factors in human IBD and in experimental models.
Methods: Human colonic epithelial cells (Caco2BBE) were used to investigate effects of inflammatory mediators on OCTN2 activity and expression. Apical membrane expression of OCTN2 was assessed by surface biotinylation. Rag-1-/-deficient mice were used to determine the potential role of adaptive immune cells in the regulation of intestinal OCTN2 expression. C57Bl/6 mice were treated with the pro-inflammatory cytokines, IFN- and TNF-, to determine expression and activity of OCTN2. OCTN2 expression in human IBD specimens was assessed by Western blotting and immunohistochemistry.
Results: OCTN2 activity and expression are regulated by the state of intestinal inflammation. OCTN2 expression in colonic tissues of Rag-1-/-deficient mice was significantly reduced. Treatment with IFN- and TNF- increased intestinal OCTN2 expression, particularly in the colon. IFN- increased both total and apical membrane expression of OCTN2, whereas TNF- stimulated apical expression. Similar results were observed in Caco2BBE cells. Colonic epithelial OCTN2 expression was increased in actively inflamed areas of both Crohn’s disease and ulcerative colitis.
Conclusions: Intestinal epithelial OCTN2 expression is increased by intestinal inflammation, most likely through increased levels of proinflammatory cytokines. These findings suggest that OCTN2 may be involved in the restoration of intestinal homeostasis under conditions of inflammation-associated stress.
