AbstractMortality and cytokine production associated with disease models mediated by TNF- and IFN-γ were studied in mice lacking IFN regulatory factor-1 (IRF-1). IRF-1 knockout (KO) mice showed no mortality after the injection of a dose of LPS lethal in intact control mice (LD95). KO mice showed lower circulating levels of TNF and IFN-γ than controls. KO mice also showed lower TNF and IFN-γ mRNA in the spleen or liver than controls. KO mice had smaller spleens than controls, which contained similar percentage but lower absolute count of macrophages and lower percentage and absolute count of NK cells. IRF-1 KO mice survived longer than controls after the coinjection of LPS and galactosamine. IRF-1 KO mice also showed less mortality than controls after the injection of Con A and in a model of cerebral malaria. After the injection of a lethal dose of TNF (LD88), mortality was similar between KO and intact mice. Mortality was also similar after the coinjection of two nonlethal doses of TNF and IFN-γ, a lethal combination (LD100). This study shows that the lack of IRF-1 protects against the mortality associated with disease models mediated by TNF and IFN-γ but has no effect on the mortality directly induced by TNF and IFN-γ. The lack of IRF-1 appears to result in impaired production of TNF and IFN-γ, reflecting a down-regulation of gene expression in the liver and spleen as well as a reduction in the number of splenic cells.