title: MicroRNA regulation of intestinal epithelial tight junction permeability.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Ye
authors.forename: Shuhong
authors.initials: S
authors.lastname: Guo
authors.forename: Rana
authors.initials: R
authors.lastname: Al-Sadi
authors.forename: Thomas Y
authors.initials: TY
authors.lastname: Ma
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D018938:Caco-2 Cells; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007444:Inulin / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D062793:Occludin; D020320:Oligoribonucleotides, Antisense / Q000378:metabolism; D010539:Permeability; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C531907:MIRN122 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007444:Inulin