Source:http://linkedlifedata.com/resource/pubmed/id/16979778
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| Predicate | Object |
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| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
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| pubmed:dateCreated |
2006-10-4
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| pubmed:abstractText |
Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ. In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-alpha (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1-/- mice but markedly decreased in jnk2-/- mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2-/- mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2-/- mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1-/- mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity. [Abstract reproduced by permission of J Biol Chem 2006;281:15258-67].
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:status |
PubMed-not-MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
0168-8278
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
45
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
762-4
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| pubmed:year |
2006
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| pubmed:articleTitle |
The role of JNK2 in toxic liver injury.
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| pubmed:affiliation |
Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
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| pubmed:publicationType |
Journal Article
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