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M512953200v1
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Papers In Press, published online ahead of print March 29, 2006
J. Biol. Chem, 10.1074/jbc.M512953200
Submitted on December 5, 2005
Accepted on March 29, 2006

TNF-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, and Mark J. Czaja

Dept. of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461

Corresponding Author: czaja{at}aecom.yu.edu

In vitro studies of hepatocytes have implicated overactivation 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 overactivation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity.


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