Protection against the mortality associated with disease models mediated by TNF and IFN-gamma in mice lacking IFN regulatory factor-1

Mortality and cytokine production associated with disease models mediated b y TNF- and IFN-gamma 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 c irculating levels of TNF and IFN-gamma than controls. KO mice also showed l ower TNF and IFN-gamma mRNA in the spleen or liver than controls. KO mice h ad smaller spleens than controls, which contained similar percentage but lo wer absolute count of macrophages and lower percentage and absolute;count o f NE; cells. IRF-1 KO mice survived longer than controls after the coinject ion of LPS and galactosamine, IFN-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 b etween KO and intact mice. Mortality was also similar after the coinjection of two nonlethal doses of TNF and IFN-gamma, a lethal combination (LD100). This study shows that the lark of IRF-1 protects against the mortality ass ociated with disease models mediated by TNF and IFN-gamma but has no effect on the mortality directly induced by TNF and IFN-gamma, The lack of IRF-1 appears to result in impaired production of TNF and IFN-gamma, reflecting a down-regulation of gene expression in the liver and spleen as well as a re duction in the number of splenic cells.