Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice.
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.
Dejager
Lien
L
Department for Molecular Biomedical Research, Ghent University, Technologiepark 927, VIB, B-9052 Ghent, Belgium.
Libert
Claude
C
D000818:Animals; D000906:Antibodies / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology; D005260:Female; D005688:Galactosamine / Q000378:metabolism*; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D007369:Interferon Inducers / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000633:toxicity*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D051193:Toll-Like Receptors / Q000378:metabolism; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000906:Antibodies; D007369:Interferon Inducers; D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D051193:Toll-Like Receptors; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D005688:Galactosamine; D011070:Poly I-C