Induction of Hepatitis by JNK-Mediated Expression of TNF-a

摘要

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 Jnkl 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 associ_ated with markedly reduced expression of TNF-a. These data indicate that JNK is required for TNF-a expression but not for TNF-a-stimulated death of hepatocytes. Indeed, TNF-a 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.