Differential roles of JNK in ConA/GalN and ConA-induced liver injury in mice

Hong Min Ni, Xiaoyun Chen, Wen Xing Ding, Marcus Schuchmann, Xiao-Ming Yin

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Abstract

Tumor necrosis factor-α-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 NH 2-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 FLIPL, 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-α-mediated liver injury.

Original languageEnglish (US)
Pages (from-to)962-972
Number of pages11
JournalAmerican Journal of Pathology
Volume173
Issue number4
DOIs
StatePublished - Oct 2008
Externally publishedYes

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Galactosamine
Cell Death
Phosphotransferases
Liver
Wounds and Injuries
Apoptosis
Hepatocytes
Tumor Necrosis Factor-alpha
Caspase 8
Caspases
Transgenic Mice

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Differential roles of JNK in ConA/GalN and ConA-induced liver injury in mice. / Ni, Hong Min; Chen, Xiaoyun; Ding, Wen Xing; Schuchmann, Marcus; Yin, Xiao-Ming.

In: American Journal of Pathology, Vol. 173, No. 4, 10.2008, p. 962-972.

Research output: Contribution to journalArticle

Ni, Hong Min ; Chen, Xiaoyun ; Ding, Wen Xing ; Schuchmann, Marcus ; Yin, Xiao-Ming. / Differential roles of JNK in ConA/GalN and ConA-induced liver injury in mice. In: American Journal of Pathology. 2008 ; Vol. 173, No. 4. pp. 962-972.
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