Induction of hepatitis by JNK-mediated expression of TNF-alpha.
Madhumita Das, Guadalupe Sabio, Feng Jiang, Mercedes Rincón, Richard A Flavell, Roger J Davis
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell 2009 Jan 23
The c-Jun NH(2)-terminal kinase (JNK) signaling pathway has been implicated in the development of tumor necrosis factor (TNF)-dependent hepatitis. JNK may play a critical role in hepatocytes during TNF-stimulated cell death in vivo. To test this hypothesis, we examined the phenotype of mice with compound disruption of the Jnk1 and Jnk2 genes. Mice with loss of JNK1/2 expression in hepatocytes exhibited no defects in the development of hepatitis compared with control mice, whereas mice with loss of JNK1/2 in the hematopoietic compartment exhibited a profound defect in hepatitis that was associated with markedly reduced expression of TNF-alpha. These data indicate that JNK is required for TNF-alpha expression but not for TNF-alpha-stimulated death of hepatocytes. Indeed, TNF-alpha induced similar hepatic damage in both mice with hepatocyte-specific JNK1/2 deficiency and control mice. These observations confirm a role for JNK in the development of hepatitis but identify hematopoietic cells as the site of the essential function of JNK.
Citation
Madhumita Das, Guadalupe Sabio, Feng Jiang, Mercedes Rincón, Richard A Flavell, Roger J Davis. Induction of hepatitis by JNK-mediated expression of TNF-alpha. Cell. 2009 Jan 23;136(2): 249-60
PMID: 19167327
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