Caspase-1 is not involved in experimental hepatitis in mouse

Experimental hepatitis induced by tumor necrosis factor in D-(+)-galactosam ine-sensitized mice or by an agonistic anti-Fas antibody in normal mice is accompanied by dramatic apoptosis of hepatocytes, Apoptosis is the final re sult of activation of a cascade of caspases, We used caspase-1(-/-) mice, g enerated by gene targeting, to study the role of this protease in TNF- and anti-Fas-induced lethal hepatitis. We found that mutant mice exhibited the typical caspase-1(-/-) phenotype, since they resisted to a lethal injection of LPS and released no interleukin-1 beta in the circulation, in contrast to wild-type littermates. When caspase-1(-/-) mice were challenged with dif ferent doses of tumor necrosis factor/D-(+)-galactosamine or with anti-Fas, no increased survival was observed compared with control mice. Furthermore , apoptosis in the livers of these mice and serum levels of alanine aminotr ansferase were not reduced. These data indicate that caspase-1 deficiency d oes not lead to reduced apoptosis in these models, either because caspase-1 is irrelevant in this model or because of functional redundancy. (C) 1999 Federation of European Biochemical Societies.