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Published on: January 5, 2017
MicroRNA-146b improves intestinal injury in mouse colitis by activating nuclear factor-κB and improving epithelial
Toshie Nata1, Mikihiro Fujiya, Nobohiro Ueno
1Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
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.
