Published online Feb 14, 2017. doi: 10.3748/wjg.v23.i6.976
Peer-review started: July 1, 2016
First decision: August 19, 2016
Revised: November 27, 2016
Accepted: December 16, 2016
Article in press: December 19, 2016
Published online: February 14, 2017
To explore the mechanism by which microRNA-155 (miR-155) regulates the pathogenesis of experimental colitis.
A luciferase assay was performed to confirm the binding of miR-155 to the SHIP-1 3’-UTR. MiR-155 mimics, negative controls and SHIP-1 expression/knockdown vectors were established and then utilized in gain- and loss-of-function studies performed in raw264.7 cells and primary bone marrow-derived macrophages (BMDMs). Thereafter, dextran sulfate sodium (DSS)-induced colitis mouse model with or without antagomiR-155 treatment was established, and the levels of miR-155 and SHIP-1, as well as the pro-inflammatory capabilities, were measured by western blot, quantitative polymerase chain reaction, and immunohistochemistry.
MiR-155 directly bound to the 3’-UTR of SHIP-1 mRNA and induced a significant decrease in SHIP-1 expression in both raw264.7 cells and primary BMDMs. MiR-155 markedly promoted cell proliferation and pro-inflammatory secretions including IL-6, TNF-α, IL-1β, and IFN-γ, whereas these effects could be reversed by the restoration of SHIP-1 expression. In vivo studies showed that antagomiR-155 administration could alleviate DSS-induced intestinal inflammation in Balb/c mice. Moreover, significantly increased SHIP-1 expression, as well as decreased Akt activation and inflammatory response, were observed in the antagomiR-155-treated mice.
MiR-155 promotes experimental colitis by repressing SHIP-1 expression. Thus, the inhibition of miR-155 might be a promising strategy for therapy.
Core tip: Our present study identifies SHIP-1 as the functional target of microRNA-155 (miR-155) in macrophages. The up-regulation of miR-155 during colitis led to a significant decrease in SHIP-1 expression as well as a marked enhancement in cell proliferation and pro-inflammatory secretions, whereas the restoration of SHIP-1 expression partly reversed these changes. We further confirmed that antagomiR-155 treatment effectively alleviates dextran sulfate sodium-induced intestinal inflammation in mice, correlated with a significant elevation in SHIP-1 expression levels. Our findings indicate a novel mechanism by which miR-155 influences colitis progression.