Reduced susceptibility of nonobese diabetic mice to TNF-alpha and D-galactosamine-mediated hepatocellular apoptosis and lethality.
Nonobese diabetic (NOD/LtJ or NOD) mice are resistant to doses of LPS and D-galactosamine that uniformly produce lethality in C57BL/6J (B6) mice (p < 0.01). Liver caspase-3-like activity, serum transaminase levels (both p < 0.05), and the numbers of apoptotic liver nuclei were also reduced in NOD compared with B6 mice treated with LPS (100 ng) and D-galactosamine (8 mg). NOD mice were also at least 100-fold more resistant to recombinant human TNF-alpha and D-galactosamine treatment than B6 mice (p < 0.001). Binding of recombinant human TNF-alpha to splenocytes from NOD mice was similar to that seen in B6 mice, suggesting that the defect in responsiveness was not due to an inability of recombinant human TNF-alpha to bind the NOD TNF type 1 (p55) receptor. Because the TNF type 1 (p55) receptor shares a common signaling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas agonist antibody, Jo-2. Surprisingly, NOD mice were as sensitive as B6 mice to Fas-induced lethality and hepatic injury. In addition, primary hepatocytes isolated from NOD mice and cultured in vitro in the presence of D-galactosamine with or without TNF-alpha were found to be resistant to apoptosis and cytotoxicity when compared with B6 mice. In contrast, Jo-2 treatment produced similar increases in caspase-3 activity and cytotoxicity in primary hepatocytes from NOD and B6 mice. The resistance to LPS- and TNF-alpha-mediated lethality and hepatic injury in D-galactosamine-sensitized NOD mice is apparently due to a post-TNFR binding defect, and independent of signaling pathways shared with Fas.
Bahjat
F R
FR
Departments of. Surgery, Pathology, Pediatrics, and Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Dharnidharka
V R
VR
Fukuzuka
K
K
Morel
L
L
Crawford
J M
JM
Clare-Salzler
M J
MJ
Moldawer
L L
LL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000401:mortality* / Q000473:pathology*; D004198:Disease Susceptibility; D005260:Female; D005434:Flow Cytometry; D005688:Galactosamine / Q000502:physiology* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000633:toxicity; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005688:Galactosamine