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Gastroenterology. 2011 Oct;141(4):1323-33. doi: 10.1053/j.gastro.2011.07.005. Epub 2011 Jul 18.

MicroRNA regulation of intestinal epithelial tight junction permeability.

Author information

1
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

Abstract

BACKGROUND & AIMS:

Defects in the intestinal epithelial tight junction (TJ) barrier contribute to intestinal inflammation. A tumor necrosis factor (TNF)-α-induced 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-α-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.

CONCLUSIONS:

TNF-α 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.

PMID:
21763238
PMCID:
PMC3724217
DOI:
10.1053/j.gastro.2011.07.005
[Indexed for MEDLINE]
Free PMC Article

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