Abstract
Conserved molecular patterns of microbial pathogens, such as lipopolysaccharide (LPS) and cytosine-phosphate-guanine (CpG) DNA motifs are important signals for receptor-mediated activation of innate immune cells. It has been shown that the liver-specific transcription-blocking d-galactosamine (D-GalN) severely sensitizes to the lethal effects of LPS and CpG DNA. Lethality of LPS or CpG DNA in GalN-treated mice is entirely due to TNF-alpha, which leads to liver cell apoptosis and acute liver failure. We report that also polyinosinic-polycytidylic acid [poly(I:C)], a TLR-3 agonist, induces systemic TNF in mice. The increases of hepatic enzymes and induction of death induced by LPS, CpG DNA, and poly(I:C) in D-GalN sensitized mice are completely blocked by neutralizing anti-TNF-alpha antibodies and absent in TNF receptor p55-knockout mice. Our results provide direct evidence that poly(I:C) induces TNF-alpha in d-GalN sensitized mice, which leads to severe, acute, and TNF-dependent lethal hepatitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / immunology
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Chemical and Drug Induced Liver Injury / immunology
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Female
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Galactosamine / metabolism*
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Humans
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Hypothermia / chemically induced
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Interferon Inducers / toxicity*
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Lipopolysaccharides / immunology
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Liver / drug effects*
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Liver / immunology
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Liver / pathology
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Liver Failure / chemically induced
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Poly I-C / toxicity*
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Survival Rate
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Toll-Like Receptors / metabolism
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Tumor Necrosis Factor Decoy Receptors / genetics
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Tumor Necrosis Factor Decoy Receptors / metabolism
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Antibodies
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Interferon Inducers
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Lipopolysaccharides
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Receptors, Tumor Necrosis Factor, Type I
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Toll-Like Receptors
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Tumor Necrosis Factor Decoy Receptors
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Tumor Necrosis Factor-alpha
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recombinant human tumor necrosis factor-binding protein-1
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Galactosamine
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Poly I-C