MicroRNA-155 regulates inflammation in alcoholic liver disease via targeting SOCS1 and SHIP1 (54.15)

Abstract

Abstract Background Fatty liver and inflammation characterize alcoholic liver disease (ALD). Sensitization of liver macrophages (Kupffer cells; KCs) to gut-derived LPS and increased TNFα play a central role in ALD. MicroRNA-155 (miR) is a master regulator of inflammation. In this study we evaluated the role of miR-155 in regulating inflammation after chronic alcohol feeding. Methods C57Bl/6 female mice were fed with 5% alcohol (Liber-DeCarli diet) for 4 weeks and total liver and KCs were isolated. Results MiR-155 positively regulates TNFα and we found increased TNFα mRNA and protein in KCs of alcohol-fed mice. Furthermore increased miR-155 levels correlated with TNFα production in KCs of alcohol-fed mice. To dissect the mechanism by which miR-155 regulates TNFα in ALD, we evaluated the miR-155 target genes SOCS1, SHIP1 and IRAKM that are negative regulators of LPS signaling. We found increased miR-155 and decreased expression of SOCS1, SHIP1 and IRAKM in KCs of alcohol-fed mice. Importantly inhibition of miR-155 by using a specific miR-155 inhibitor, inhibited TNFα production in KCs of alcohol-fed mice, suggesting a role of miR-155 in TNFα regulation. C/EBPβ, another miR-155 target, regulates monocyte maturation and cytokine production. We found increased miR-155 and decreased DNA binding of C/EBPβ in livers of alcohol-fed mice. Conclusion Collectively our results indicate that alcohol induced-miR-155 contributes to inflammation via targeting multiple genes of LPS/TLR4 signaling.