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-gamma receptor negative (IFN gamma R-/-) mutant mice has enabled a more direct assessment of the role of IFN-gamma in endotoxin (lipopolysaccharide [LPS]-induced shock. We report that IFN gamma R-/- mice have an increased resistance to LPS-induced toxicity, this resistance manifesting well before the synthesis and release of LPS-induced IFN-gamma. LPS-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 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 IFN gamma R-/- 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-gamma signaling in the mutant mice, likely to combine to manifest in the resistant phenotype of IFN gamma R-/- mice to endotoxin.
Car
B D
BD
Institute of Toxicology of the Swiss Federal Institute of Technology, Zürich.
Eng
V M
VM
Schnyder
B
B
Ozmen
L
L
Huang
S
S
Gallay
P
P
Heumann
D
D
Aguet
M
M
Ryffel
B
B
D000818:Animals; D001835:Body Weight; D004731:Endotoxins; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008969:Molecular Sequence Data; D017471:Receptors, Interferon / Q000172:deficiency* / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000096743:Interferon gamma Receptor
D004731:Endotoxins; D008070:Lipopolysaccharides; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C044101:endotoxin, Escherichia coli