Con A-induced hepatitis (Con A-hepatitis) is a hepatitis model in which hepatic injury is supposed to be caused by cytokines from activated T cells. To elucidate the pathogenesis of this disease, we analyzed the roles of IFN-gamma and TNF-alpha using deficient mice of these cytokines. Development of hepatitis was reduced significantly in IFN-gamma(-/-) mice, while susceptibility of TNF-alpha(-/-) mice was not changed. Interestingly, apoptotic cell death was observed in the affected livers of control or TNF-alpha(-/-) mice, but not in those of IFN-gamma(-/-) mice. Fas mRNA expression was increased in the livers of hepatitis mice, but less abundantly in those of IFN-gamma(-/-) mice. Since apoptosis of liver cells was rarely observed in Con A-treated lpr/lpr mice, involvement of the Fas-Fas ligand system in this apoptotic process was suggested. These observations suggest that IFN-gamma plays a central role in Con A-hepatitis by activating Fas-induced apoptosis of liver cells.