Interleukin-32γ attenuates ethanol-induced liver injury by the inhibition of cytochrome P450 2E1 expression and inflammatory responses

Alcohol abuse and alcoholism lead to alcoholic liver disease (ALD), which is a major type of chronic liver disease worldwide. Interleukin-32 (IL-32) is a novel cytokine involved in inflammation and cancer development. However, the role of IL-32 in chronic liver disease has not been reported. In the present paper, we tested the effect of IL-32 gamma on ethanol-induced liver injury in IL-32 gamma-overexpressing transgenic mice (IL-32 gamma mice) after chronic ethanol feeding. Male C57BL/6 and IL-32 gamma mice (10-12 weeks old) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 6 weeks. IL-32 gamma-transfected HepG2 and Huh7 cells, as well as primary hepatocytes from IL-32 gamma mice, were treated with or without ethanol. The hepatic steatosis and damage induced by ethanol administration were attenuated in IL-32 gamma mice. Ethanol-induced cytochrome P450 2E1 expression and hydrogen peroxide levels were decreased in the livers of IL-32 gamma mice, primary hepatocytes from IL-32 gamma mice and IL-32 gamma-overexpressing human hepatic cells. The ethanol-induced expression levels of cyclo-oxygenase-2 (COX-2) and IL-6 were reduced in the livers of IL-32 gamma mice. Because nuclear transcription factor kappa B (NF-kappa B) is a key redox transcription factor of inflammatory responses, we examined NF-kappa B activity. Ethanol-induced NF-kappa B activities were significantly lower in the livers of IL-32 gamma mice than in wild-type (WT) mice. Furthermore, reduced infiltration of natural killer cells, cytotoxic T-cells and macrophages in the liver after ethanol administration was observed in IL-32 gamma mice. These data suggest that IL-32 gamma prevents ethanol-induced hepatic injury via the inhibition of oxidative damage and inflammatory responses.