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

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

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Department for Molecular Biomedical Research, Ghent University, Technologiepark 927, VIB, B-9052 Ghent, Belgium.


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.

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