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 co mpared with B6 mice treated with LPS (100 ng) and D-galactosamine (8 mg), N OD mite 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 r ecombinant human TNF-<alpha> to splenocytes from NOD mice was similar to th at seen in B6 mice, suggesting that the defect in responsiveness was not du e 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 sign aling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas ag onist antibody, Jo-2. Surprisingly, NOD mice were as sensitive as B6 mice t o Fas-induced lethality and hepatic injury. In addition, primary hepatocyte s isolated from NOD mice and cultured in vitro in the presence of D-galacto samine with or without TNF-alpha were found to be resistant to apoptosis an d cytotoxicity when compared with B6 mice. In contrast, Jo-2 treatment prod uced similar increases in caspase-3 activity and cytotoxicity in primary he patocytes from NOD and B6 mice. The resistance to LPS- and TNF-alpha -media ted 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.