Differential roles of JNK in ConA/GalN and ConA-induced liver injury in mice.
Tumor necrosis factor-alpha-mediated liver injury can be induced by several different means; however, the signaling events and mechanisms of cell death are likely different. We investigated the mechanism of both apoptotic and necrotic hepatocyte cell death as well as the role of c-Jun NH2-terminal kinase (JNK) in the ConA and ConA/D-galactosamine (GalN) models of murine liver injury. ConA alone induced primarily necrotic cell death with no caspase activation, whereas ConA/GalN induced apoptosis in addition to necrotic cell death. The bi-modal death pattern in the ConA/GalN model was confirmed by the use of transgenic mice expressing a dominant-negative form of Fas-associated death domain in which the mice were resistant to apoptotic but not necrotic cell death. JNK1 and, more significantly, JNK2 participated in the induction of hepatocyte apoptosis in response to ConA/GalN. Deletion of JNK led to the stabilization of FLIP L, reduced caspase-8 activation, decreased Bid cleavage, and inhibition of the mitochondrial apoptosis pathway. In contrast, JNK did not participate in necrotic death induced by ConA either alone or in combination with GalN. As such, JNK-deficient mice remained susceptible to necrotic liver injury in both model systems. Thus, ConA and ConA/GalN mouse models induce liver injury with different mechanisms of cell death, and JNK contributes to apoptotic but not necrotic cell death. These findings further elucidate the specific pathways involved in tumor necrosis factor-alpha-mediated liver injury.
Ni
Hong-Min
HM
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Chen
Xiaoyun
X
Ding
Wen-Xing
WX
Schuchmann
Marcus
M
Yin
Xiao-Ming
XM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005688:Galactosamine; D017353:Gene Deletion; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008107:Liver Diseases / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation / Q000187:drug effects
D051023:BH3 Interacting Domain Death Agonist Protein; D053200:Fas-Associated Death Domain Protein; D050505:Mutant Proteins; D003208:Concanavalin A; D005688:Galactosamine; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8
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