Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury.
Tumor necrosis factor (TNF)-alpha-induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF-alpha exerts a variety of effects that are mediated mainly by TNF-receptor 1 (TNF-R1) in cell death. The activation of TNF-R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro-death Bcl-2 family proteins, reactive oxygen species, C-Jun NH2-terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF-alpha-induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.
Ding
Wen-Xing
WX
Department of Pathology, University of Pittsburgh, School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Yin
Xiao-Ming
XM
D000818:Animals; D017209:Apoptosis; D002401:Cathepsin B / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000293:injuries*; D008107:Liver Diseases / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494772:BAK1 protein, human; D002518:Ceramides; D008565:Membrane Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D002401:Cathepsin B