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

Department of Surgery, University of Florida College of Medicine Gainesville, Florida, USA, Department of Inflammation, Amgen, Inc., Thousand Oaks, California, USA

Caroline Oberholzer

Department of Surgery, University of Florida College of Medicine Gainesville, Florida, USA, Department of Inflammation, Amgen, Inc., Thousand Oaks, California, USA

F.R. Bahjat

Department of Surgery, University of Florida College of Medicine Gainesville, Florida, USA, Department of Inflammation, Amgen, Inc., Thousand Oaks, California, USA

Carl K. Edwards

Department of Surgery, University of Florida College of Medicine Gainesville, Florida, USA, Department of Inflammation, Amgen, Inc., Thousand Oaks, California, USA,

Lyle L. Moldawer

Department of Surgery, University of Florida College of Medicine Gainesville, Florida, USA, Department of Inflammation, Amgen, Inc., Thousand Oaks, California, USA, moldawer{at}surgery.ufl.edu

Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent upon endogenously produced TNF-. 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- acting primarily through the p55 TNF receptor. Transgenic mice expressing null forms of TNF-, the p55 receptor, or expressing only a cell-associated form of TNF- 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 LPSand 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- and p55 TNF receptor signaling in the hepatocyte apoptosis and lethality associated with lipopolysaccharide and D-galactosamine administration.

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