title: Differential requirement for c-Jun NH2-terminal kinase in TNFalpha- and Fas-mediated apoptosis in hepatocytes.
abstract: The c-Jun NH2-terminal kinase (JNK) is involved in the regulation of cell death, but its role in tumor necrosis factor (TNF)-alpha- and Fas-mediated apoptosis in primary cells is not well defined. In primary rat hepatocytes expressing an IkappaB superrepressor, the JNK inhibitor SP600125 strongly decreased TNF-alpha-induced cell death, caspase 3 activation, and DNA laddering. In contrast, SP600125 did not rescue mouse hepatocytes from Fas-induced apoptosis. Apoptosis in mouse hepatocytes, induced by human TNF-alpha, was blocked by SP600125, indicating that TNF-receptor (TNF-R) 1-mediated JNK activation is important for TNF-alpha-induced death. However, mouse TNF-alpha was more efficient than human TNF-alpha in activating JNK and killing mouse hepatocytes, suggesting that TNF-R1 and TNF-R2 cooperate in JNK activation and apoptosis. SP600125 rescued actinomycin D-pretreated hepatocytes and hepatocytes expressing a dominant negative c-Jun from TNF-alpha, indicating that JNK exerts its proapoptotic effect independently of transcription and c-Jun. SP600125 delayed the mitochondrial permeability transition, inhibited cytochrome c release and prevented bid degradation after TNF-alpha, suggesting that JNK-regulated proapoptotic factors act upstream of the mitochondria. Moreover, overexpression of JNK1 activated a mitochondrial death pathway in hepatocytes, albeit less efficiently than TNF-alpha. This study demonstrates that JNK augments TNF-alpha-induced apoptosis in hepatocytes through a signaling pathway that is distinct from the pathway by which it regulates proliferation.
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. rfs2102@columbia.edu
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.forename: Ting
authors.initials: T
authors.lastname: Qian
authors.forename: Brydon L
authors.initials: BL
authors.lastname: Bennett
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D020672:I-kappa B Proteins / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008954:Models, Biological; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D015703:Antigens, CD; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D020672:I-kappa B Proteins; D007473:Ion Channels; D008562:Membrane Glycoproteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases