Journal
CELL
Volume 136, Issue 2, Pages 249-260Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.11.017
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [R01 CA065861, R01 CA065861-14] Funding Source: Medline
- NIAID NIH HHS [R01 AI051454] Funding Source: Medline
- NIDDK NIH HHS [P30 DK032520-26, P30 DK 32520, P30 DK032520] Funding Source: Medline
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The c-Jun NH2-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.
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