abstract
- Defects in the intestinal epithelial tight junction (TJ) barrier contribute to intestinal inflammation. A tumor necrosis factor (TNF)-?-induced increase in intestinal TJ permeability contributes to the intestinal TJ barrier defect in inflammatory disorders. We investigated the mechanisms by which TNF-? induces occludin depletion and an increase in intestinal TJ permeability.We assessed intestinal TJ barrier function using intestinal epithelial model systems: filter-grown Caco-2 monolayers and recycling perfusion studies of mouse small intestine.TNF-? caused a rapid increase in expression of microRNA (miR)-122a in enterocytes, cultured cells, and intestinal tissue. The overexpressed miR-122a bound to a binding motif at the 3'-untranslated region of occludin messenger RNA (mRNA) to induce its degradation; mRNA degradation depleted occludin from enterocytes, resulting in increased intestinal TJ permeability. Transfection of enterocytes with an antisense oligoribonucleotide against miR-122a blocked the TNF-?-induced increase in enterocyte expression of miR-122a, degradation of occludin mRNA, and increase in intestinal permeability. Overexpression of miR-122a in enterocytes using pre-miR-122a was sufficient to induce degradation of occludin mRNA and an increase in intestinal permeability.TNF-? regulates intestinal permeability by inducing miR-122a-mediated degradation of occludin mRNA. These studies show the feasibility of therapeutically targeting miR-122a in vivo to preserve the intestinal barrier.Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.