Interferon γ receptor deficient mice are resistant to endotoxic shock

Abstract

Antibody neutralization studies have established interferon γ (IFN-γ) as a critical mediator of endotoxic shock. The advent of IFN-γ receptor negative (IFNγR-/-) mutant mice has enabled a more direct assessment of the role of IFN-γ in endotoxin (lipopolysaccharide [LPS]-induced shock. We report that IFNγR-/- mice have an increased resistance to LPS-induced toxicity, this resistance manifesting well before the synthesis and release of LPS-induced IFN-γ. LPS-induced lymphopenia, thrombocytopenia, and weight loss seen in wild-type mice were attenuated in IFNγR-/- mice. IFNγR-/- mice tolerated 100-1,000 times more LPS than the minimum lethal dose for wild- type mice in a D-galactosamine (D-GalN)/LPS model. Serum tumor necrosis factor (TNF) levels were 10-fold reduced in mutant mice given LPS or LPS/D- GalN. Bone marrow and splenic macrophages from IFNγR-/- mice had a four- to sixfold decreased LPS-binding capacity which correlated with similar reduction in CD14. Serum from mutant mice reduced macrophage LPS binding by a further 50%, although LPS binding protein was only 10% reduced. The expression of TNF receptor I (p55) and II (p75) was identical between wild- type and mutant mice. Thus, depressed TNF synthesis, diminished expression of CD14, and low plasma LPS-binding capacity, in addition to blocked IFN-γ signaling in the mutant mice, likely to combine to manifest in the resistant phenotype of IFNγR-/- mice to endotoxin.