Reduced susceptibility of nonobese diabetic mice to TNF-α and D-galactosamine-mediated hepatocellular apoptosis and lethality

F. R. Bahjat, V. R. Dharnidharka, K. Fukuzuka, L. Morel, J. M. Crawford, M. J. Clare-Salzler, L. L. Moldawer

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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-α and D-galactosamine treatment than B6 mice (p < 0.001). Binding of recombinant human TNF-α 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-α 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-α 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-α-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.

Original languageEnglish (US)
Pages (from-to)6559-6567
Number of pages9
JournalJournal of Immunology
Volume165
Issue number11
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Bahjat, F. R., Dharnidharka, V. R., Fukuzuka, K., Morel, L., Crawford, J. M., Clare-Salzler, M. J., & Moldawer, L. L. (2000). Reduced susceptibility of nonobese diabetic mice to TNF-α and D-galactosamine-mediated hepatocellular apoptosis and lethality. Journal of Immunology, 165(11), 6559-6567.