Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, IFN-, in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine and choline-deficient high fat (MCDHF) diet to both wild-type and IFN--deficient mice, the liver histology, expression of genes encoding inflammatory cytokines and fibrosis-related markers were examined. To analyze the effects of IFN- on Kupffer cells in vitro, we examined the TNF-α production by a mouse macrophage cell line. 42 days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis and inflammation in wild-type mice. However, the IFN--deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of TNF-α, TGF-β1, iNOS, IL-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN--deficient mice. 70 days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN--deficient mice. The expression levels of fibrosis-related genes, α-SMA, type-I collagen, TIMP-1 and MMP-2 were dramatically increased in wild-type mice, while they were significantly suppressed in IFN--deficient mice. Moreover, in vitro experiments showed that when RAW 264.7 macrophages were treated with IFN-, they produced TNF-α in a dose-dependent manner. The present study showed that IFN- deficiency might inhibit the inflammatory response of macrophages cells, subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN- in the progression of steatohepatitis.