Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway

Yongjun Wang, Rajat Singh, Jay H. Lefkowitch, Raina M. Rigoli, Mark J. Czaja

Research output: Contribution to journalArticle

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Abstract

In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-α (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.

Original languageEnglish (US)
Pages (from-to)15258-15267
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number22
DOIs
StatePublished - Jun 2 2006

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Caspase 8
Poisons
Liver
Tumor Necrosis Factor-alpha
Chemical activation
Phosphotransferases
Wounds and Injuries
Galactosamine
Lipopolysaccharides
Caspases
Apoptosis
Caspase 7
Poly(ADP-ribose) Polymerases
JNK Mitogen-Activated Protein Kinases
Tumor Necrosis Factor Receptors
Ablation
Cytochromes c
Caspase 3
Hepatocytes
Protein Isoforms

ASJC Scopus subject areas

  • Biochemistry

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Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. / Wang, Yongjun; Singh, Rajat; Lefkowitch, Jay H.; Rigoli, Raina M.; Czaja, Mark J.

In: Journal of Biological Chemistry, Vol. 281, No. 22, 02.06.2006, p. 15258-15267.

Research output: Contribution to journalArticle

Wang, Yongjun ; Singh, Rajat ; Lefkowitch, Jay H. ; Rigoli, Raina M. ; Czaja, Mark J. / Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 22. pp. 15258-15267.
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