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and D-Galactosamine-Mediated Hepatocellular Apoptosis and Lethality1
Departments of
*
Surgery,
Pathology,
Pediatrics, and
Medicine, University of Florida College of Medicine, Gainesville, FL 32610
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-
and
D-galactosamine treatment than B6 mice
(p < 0.001). Binding of recombinant human TNF-
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- 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- 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--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.
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