Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: Role of STAT3

摘要

Interleukin-22 (IL-22), a recently identified member of the IL-10 family of cytokines that is produced by Th17 and NK cells, plays an important role in controlling bacterial infection, homeostasis, and tissue repair. In this paper, we tested the effect of IL-22 on alcohol-induced liver injury in a murine model of chronic-binge ethanol feeding. Feeding male C57BL/6 mice with a Lieber-DeCarli diet containing 5% ethanol for 10 days, followed by a single dose of 5g/kg ethanol gavage, induces significant fatty liver and liver injury with peak serum levels of about 250 IU/L ALT and 420 IU/L AST 9 hours post gavage. Moreover, chronic-binge ethanol administration increases expression of hepatic and serum inflammatory cytokines and hepatic oxidative stress. Using this model, we demonstrate that treatment with IL-22 recombinant protein activates hepatic STAT3 and ameliorates alcoholic fatty liver, liver injury, and hepatic oxidative stress. Administration with IL-22 adenovirus also prevents alcohol-induced steatosis and liver injury. Deletion of STAT3 in hepatocytes abolishes the hepatoprotection provided by IL-22 in alcoholic liver injury. In addition, IL-22 treatment downregulates the hepatic expression of fatty acid transport protein, but upregulates several antioxidant, antiapoptotic genes, and antimicrobial genes. Finally, expression of IL-22R1 is upregulated while IL-22 is undetectable in the livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. In conclusion, chronic-binge ethanol feeding may be a useful model to study the early stage of alcoholic liver injury. IL-22 treatment could be a potential therapeutic option to ameliorate alcoholic liver disease due to its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects with the added benefit of potentially few side effects.