INTERFERON-GAMMA RECEPTOR-DEFICIENT MICE ARE RESISTANT TO ENDOTOXIC-SHOCK

Antibody neutralization studies have established interferon gamma (IFN -gamma) as a critical mediator of endotoxic shock. The advent of IFN-g amma receptor negative (IFN gamma R-/-) mutant mice has enabled a more direct assessment of the role of IFN-gamma in endotoxin (lipopolysacc haride [LPS]-induced shock. We report that IFN gamma R-/- mice have an increased resistance to LPS-induced toxicity, this resistance manifes ting well before the synthesis and release of LPS-induced IFN-gamma. L PS-induced lymphopenia, thrombocytopenia, and weight loss seen in wild -type mice were attenuated in IFN gamma R-/- mice. IFN gamma R-/- mice tolerated 100-1,000 times more LPS than the minimum lethal dose for w ild-type mice in a D-galactosamine (D-GalN)/LPS model. Serum tumor nec rosis factor (TNF) levels were 10-fold reduced in mutant mice given LP S or LPS/D-GalN. Bone marrow and splenic macrophages from IFN gamma R- /- mice had a four- to sixfold decreased LPS-binding capacity which co rrelated with similar reduction in CD14. Serum from mutant mice reduce d macrophage LPS binding by a further 50%, although LPS binding protei n 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-bind ing capacity, in addition to blocked IFN-gamma signaling in the mutant mice, likely to combine to manifest in the resistant phenotype of IFN gamma R-/- mice to endotoxin.