Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice

Cytokine. 2008 Apr;42(1):55-61. doi: 10.1016/j.cyto.2008.01.014. Epub 2008 Mar 10.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Chemical and Drug Induced Liver Injury / immunology
  • Female
  • Galactosamine / metabolism*
  • Humans
  • Hypothermia / chemically induced
  • Interferon Inducers / toxicity*
  • Lipopolysaccharides / immunology
  • Liver / drug effects*
  • Liver / immunology
  • Liver / pathology
  • Liver Failure / chemically induced
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / toxicity*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Survival Rate
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor Decoy Receptors / genetics
  • Tumor Necrosis Factor Decoy Receptors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antibodies
  • Interferon Inducers
  • Lipopolysaccharides
  • Receptors, Tumor Necrosis Factor, Type I
  • Toll-Like Receptors
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha
  • recombinant human tumor necrosis factor-binding protein-1
  • Galactosamine
  • Poly I-C