Genetic determinants of lipopolysaccharide and D-galactosamine-mediated hepatocellular apoptosis and lethality

A. Oberholzer, C. Oberholzer, F. R. Bahjat, C. K. Edwards, L. L. Moldawer

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent upon endogenously produced TNF-α. Unlike the response to high dose lipopolysaccharide alone, death in this model is a direct result of hepatocyte apoptosis. In a series of recent studies, we have demonstrated that mortality and hepatic injury following lipopolysaccharide administration in D-galactosamine-sensitized mice is dependent upon secreted 17 kDa TNF-α acting primarily through the p55 TNF receptor. Transgenic mice expressing null forms of TNF-α, the p55 receptor, or expressing only a cell-associated form of TNF-α exhibited no mortality and only modest liver injury when challenged with 8 mg of D-galactosamine and 100 ng of lipopolysaccharide. Although Fas ligand expression is increased in the liver, it appeared to play no significant role in outcome, since mice expressing a mutant form of Fas ligand are still sensitive to LPS- and D-galactosamine-induced lethality. Finally, we have seen significant variation in LPS- and D-galactosamine-mediated lethality among different strains of mice. The non-obese diabetic or NOD mouse is highly resistant to LPS-and D-galactosamine-induced lethality, and this appears to be secondary to a post-receptor defect in p55 TNF receptor signaling. The studies confirm an essential role for TNF-α and p55 TNF receptor signaling in the hepatocyte apoptosis and lethality associated with lipopolysaccharide and D-galactosamine administration.

Original languageEnglish (US)
Pages (from-to)375-380
Number of pages6
JournalJournal of Endotoxin Research
Volume7
Issue number5
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Molecular Biology
  • Cell Biology
  • Infectious Diseases

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