Interleukin-22 alleviates alcohol-associated hepatic fibrosis, inhibits autophagy, and suppresses the PI3K/AKT/mTOR pathway in mice.

Background: Alcohol-associated hepatic fibrosis is a widespread liver disease with no effective treatment. Recent studies have indicated that interleukin-22 (IL-22) can ameliorate alcohol-associated liver disease. However, the mechanism underlying the role of IL-22 in alcohol-associated hepatic fibrosis remains unclear. Therefore, we investigated the effect of IL-22 in a mouse model of alcohol-associated hepatic fibrosis and its underlying mechanisms.
Methods: Alcohol-associated hepatic fibrosis was induced by feeding male C57BL/6J mice with a Lieber-DeCarli liquid diet containing 4% ethyl alcohol for 8 weeks and injecting them with 5% tetrachloromethane (CCl ₄ ) intraperitoneally for the last 4 weeks. During the last 4 weeks, IL-22 was also administered. We investigated the role of IL-22 in autophagy and the PI3K/AKT/mTOR signaling pathway using a 3-methyladenine intraperitoneal injection in the mice treated with IL-22. The effects of IL-22 on alcohol-associated hepatic fibrosis, autophagy-related gene expression, and PI3K/AKT/mTOR activity were assessed using histopathology, biochemical analysis, transmission electron microscopy, quantitative real-time PCR, immunohistochemistry, and western blotting.
Results: Mice treated with ethanol and CCl ₄ displayed distinct liver injuries, including hepatocyte necrosis, inflammatory cell infiltration, and hepatic fibrosis, which were substantially attenuated by IL-22 treatment. In addition, we found that IL-22 regulated the expression of autophagy-related genes and inhibited the PI3K/AKT/mTOR pathway, as evidenced by the reduction in p-PI3K, p-AKT, and p-mTOR expression after IL-22 treatment.
Conclusions: IL-22 exerts a marked protective effect against alcohol-associated hepatic fibrosis. Its effect may be partly related to the alteration of autophagy-related gene expression and inhibition of the PI3K/AKT/mTOR pathway in the liver.
(© 2023 Research Society on Alcohol.)