MicroRNA regulation of intestinal epithelial tight junction permeability

Dongmei Ye, Shuhong Guo, Rana Al-Sadi, Thomas Ma

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

Abstract

Background & Aims: Defects in the intestinal epithelial tight junction (TJ) barrier contribute to intestinal inflammation. A tumor necrosis factor (TNF)-αinduced increase in intestinal TJ permeability contributes to the intestinal TJ barrier defect in inflammatory disorders. We investigated the mechanisms by which TNF-α induces occludin depletion and an increase in intestinal TJ permeability. Methods: We assessed intestinal TJ barrier function using intestinal epithelial model systems: filter-grown Caco-2 monolayers and recycling perfusion studies of mouse small intestine. Results: TNF-α 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-αinduced increase in enterocyte expression of miR-122a, degradation of occludin mRNA, and increase in intestinal permeability. Overexpression of miR-122a in enterocytes using premiR-122a was sufficient to induce degradation of occludin mRNA and an increase in intestinal permeability. Conclusions: TNF-α regulates intestinal permeability by inducing miR-122amediated degradation of occludin mRNA. These studies show the feasibility of therapeutically targeting miR-122a in vivo to preserve the intestinal barrier.

Original languageEnglish (US)
Pages (from-to)1323-1333
Number of pages11
JournalGastroenterology
Volume141
Issue number4
DOIs
StatePublished - Oct 2011

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'MicroRNA regulation of intestinal epithelial tight junction permeability'. Together they form a unique fingerprint.

Cite this