Genetic determinants of lipopolysaccharide and D-galactosamine-mediated hepatocellular apoptosis and lethality.
Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent upon endogenously produced TNF-alpha. 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-alpha acting primarily through the p55 TNF receptor. Transgenic mice expressing null forms of TNF-alpha, the p55 receptor, or expressing only a cell-associated form of TNF-alpha 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-alpha and p55 TNF receptor signaling in the hepatocyte apoptosis and lethality associated with lipopolysaccharide and D-galactosamine administration.
Oberholzer
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A
Department of Surgery, University of Florida College of Medicine Gainesville, Florida 32610, USA.
Oberholzer
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C
Bahjat
F R
FR
Edwards
C K
CK
Moldawer
L L
LL
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D056486:Chemical and Drug Induced Liver Injury; D004359:Drug Therapy, Combination; D005688:Galactosamine / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000473:pathology; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis; D011994:Recombinant Proteins; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases