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in Mice Lacking IFN Regulatory Factor-1
*
Amgen Inc., Thousand Oaks, CA 91320; and
Amgen Research Institute, Toronto, Ontario, Canada
Mortality and cytokine production associated with disease models
mediated by TNF- and IFN-
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- than controls. KO mice also showed lower TNF and IFN-
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-, 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- but has no
effect on the mortality directly induced by TNF and IFN-. The lack
of IRF-1 appears to result in impaired production of TNF and IFN-,
reflecting a down-regulation of gene expression in the liver and spleen
as well as a reduction in the number of splenic
cells.
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