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

The cJun NH2-terminal kinase (JNK) signaling pathway has been implicated in the development of tumor necrosis factor (TNF) -dependent hepatitis. Indeed, 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. In contrast, mice with loss of JNK1/2 in the hematopoietic compartment exhibited a profound defect in hepatitis that was associated with markedly reduced expression of TNFα. Together, these data indicate that JNK is required for TNFα expression, but JNK is not required for TNFα-stimulated death of hepatocytes. Indeed, TNFα-induced similar hepatic damage in 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.