Our laboratory has been actively studying the molecular mechanisms of alcoholic liver disease, focusing on (1) the role of interleukin-6 (IL-6) and IL-10 and their downstream signal STAT3 in alcoholic fatty liver and liver inflammation;(2) the hepatoprotective effect of IL-22 in alcoholic liver injury. IL-6/IL-10/STAT3 in alcoholic liver disease We have previously demonstrated that IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). We have also extensively investigated the role of hepatocytes-, myeloid cells-, and endothelial cells-specific STAT3 in alcoholic liver injury and inflammation. During last year, we have examined the role of IL-10 in alcoholic liver disease and nonalcoholic fatty liver disease. Compared to wild-type mice, IL-10-deficient mice had increased liver inflammation but were resistant to ethanol- or high fat diet-induced fatty liver and liver injury, which was associated with higher levels of hepatic and serum IL-6 and higher levels of STAT3 activation in the liver. An additional deletion of IL-6 or liver STAT3 restored steatosis and liver injury in IL-10-deficient mice, suggesting that the resistance of IL-10-deficient mice to ethanol-and high fat diet-induced fatty liver is due to elevation of IL-6 and subsequent activation of its downstream signaling STAT3 in the liver. Currently, we are exploring the mechanism underlying the IL-6/STAT3-mediated inhibition of steatosis in IL-10-deficient mice. Hepatoprotective effect of IL-22 in alcoholic liver injury Interleukin-22 (IL-22), a recently identified IL-10 family cytokine that is produced by Th17 cells 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 plus binge ethanol feeding. Feeding male C57/BL6 mice with Liber-Decali diet containing 5% ethanol for 10 days, followed by a single dose of 5g/kg ethanol gavage, induces significantly fatty liver and liver injury with peak serum levels of about 250 IU/L ALT and 420 IU/L AST 9 hours post gavage, and increases the expression of hepatic and serum inflammatory cytokines and hepatic oxidative stress. By using this model, we have demonstrated that treatment with IL-22 ameliorates alcoholic fatty liver, liver injury, and hepatic oxidative stress, which was also confirmed by using infection with IL-22 adenovirus. IL-22 treatment induces STAT3 activation in the liver. Deletion of STAT3 in hepatocytes abolishes the hepatoprotection of IL-22 in alcoholic liver injury. Finally, IL-22 treatment downregulates the hepatic expression of fatty acid transport protein, several antioxidant and anti-apoptotic genes, and antimicrobial genes. In conclusion, chronic plus single ethanol gavage feeding may be a useful model to study the early stage of alcoholic liver injury. IL-22 could be a potential therapeutic drug to treat alcoholic liver disease because of its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects with few side effects. In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.
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