Linked Life Data

16571730

Source:http://linkedlifedata.com/resource/pubmed/id/16571730

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
2006-5-29
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
2
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
15258-67
pubmed:dateRevised
2010-9-8
pubmed:meshHeading
pubmed-meshheading:16571730-Animals, pubmed-meshheading:16571730-Apoptosis, pubmed-meshheading:16571730-Caspase 8, pubmed-meshheading:16571730-Caspases, pubmed-meshheading:16571730-Enzyme Activation, pubmed-meshheading:16571730-Female, pubmed-meshheading:16571730-Galactosamine, pubmed-meshheading:16571730-Lipopolysaccharides, pubmed-meshheading:16571730-Liver, pubmed-meshheading:16571730-Male, pubmed-meshheading:16571730-Mice, pubmed-meshheading:16571730-Mice, Inbred C57BL, pubmed-meshheading:16571730-Mice, Knockout, pubmed-meshheading:16571730-Mitochondria, pubmed-meshheading:16571730-Mitogen-Activated Protein Kinase 8, pubmed-meshheading:16571730-Mitogen-Activated Protein Kinase 9, pubmed-meshheading:16571730-Recombinant Proteins, pubmed-meshheading:16571730-Signal Transduction, pubmed-meshheading:16571730-Tumor Necrosis Factor-alpha
pubmed:year
2006
pubmed:articleTitle
Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway.
pubmed:affiliation
Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't