MicroRNA-146b improves intestinal injury in mouse colitis by activating nuclear factor-κB and improving epithelial barrier function

J Gene Med. Jun-Jul 2013;15(6-7):249-60. doi: 10.1002/jgm.2717.

Abstract

Background: The precise role of microRNAs in inflammatory disease is not clear. The present study investigated the effect of microRNA (miR-146b) with respect to improving intestinal inflammation.

Methods: The microRNA profile in interleukin-10 deficient mice was examined using microRNA arrays and miR-146b was selected for the subsequent experiments. The expression vectors containing either the whole sequence of miR-146b or small interfering RNA for miR-146b were intraperitoneally administered to the dextran sodium sulfate (DSS)-induced colitis mouse. The expression levels of inflammation-related mediators were examined by the reverse transcriptase-polymerase chain reaction and western blotting analysis. Intestinal barrier function was evaluated by an ex vivo mannitol flux study.

Results: The overexpression of miR-146b activated the NF-κB pathway, improved epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of intestinal inflammation by miR-146b was negated by the inhibitor for the NF-κB pathway. The overexpression of miR-146b decreased the expression of siah2, which has a target sequence for miR-146b, and promoted the ubiquitination of TRAF proteins. This suggests that the up-regulation of NF-κB by miR-146b was mediated by inhibition of the ubiquitination of TRAF proteins upstream of NF-κB.

Conclusions: miR-146b improves intestinal inflammation by up-regulating NF-κB as a result of the decreased expression of siah2, which ubiquitinates TRAF proteins. Modulation of the miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation via activation of the NF-κB pathway.

Keywords: gene therapy; inflammatory bowel disease (IBD).

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Blotting, Western
  • Colitis / mortality
  • Colitis / therapy*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Immunohistochemistry
  • Intestinal Mucosa / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • MicroRNAs / pharmacology*
  • NF-kappa B / metabolism
  • Protein Binding
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Anti-Inflammatory Agents
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • NF-kappa B
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Siah2 protein, mouse
  • Ubiquitin-Protein Ligases