Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-alpha-induced liver injury.
Tumor necrosis factor-alpha (TNFalpha)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of pro-death Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNFalpha-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNFalpha in the presence of d-galactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the bid-deficient mice. Additional genetic factor(s) could further modify the dependence of TNFalpha toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNFalpha-mediated pathogenesis in vivo.
Zhao
Y
Y
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Li
S
S
Childs
E E
EE
Kuharsky
D K
DK
Yin
X M
XM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D005688:Galactosamine / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008111:Liver Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D005688:Galactosamine