Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

Abstract

Background and AimsACLF is usually associated with a precipitant in the setting of a chronically damaged liver. We aim to combine a mouse model with a pre-injured liver (Abcb4/Mdr2−/−) with a recently standardized ethanol feeding model to dissect alcohol-related inflammatory responses in this model. MethodTen (n = 64) and 15 (n = 64) week old wild-type (WT) C57BL/6 J and Abcb4−/− knock-out (KO) mice were either fed control (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an ethanol binge (4 mg/kg) (WT/EtOH and KO/EtOH groups). Hepatic mRNA levels of IL6, IFN-G, IL-1B, TGFB1, TNF-A, CCL2, HGF, CRP, RANTES, PNPLA3 and COL3A1 were evaluated using the 2−ΔΔCt method. IL6 and HGF plasma levels were quantified by ELISA. ResultsOlder mice in KO/EtOH group displayed higher IL6 expressions compared to KO/Cont, WT/EtOH and WT/Cont groups of the same age, whereas HGF did not differ. Significant over-expression of CCL2 also corresponded to the same group. Males in KO/EtOH group exhibited higher IL6 expression than females. Lipid droplets were observed in about 80% of mice challenged with ethanol. There was a profound downregulation in PNPLA3 and RANTES levels after ethanol exposure. Mean size of the LDs was inversely correlated with hepatic PNPLA3 levels. ConclusionWe propose a novel promising approach to model alcohol-related ACLI. Acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Abcb4−/− mice. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model.