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

被引:119
作者
Das, Madhumita [1 ]
Sabio, Guadalupe [1 ,2 ]
Jiang, Feng [1 ]
Rincon, Mercedes [3 ]
Flavell, Richard A. [4 ,5 ]
Davis, Roger J. [1 ,2 ]
机构
[1] Univ Massachusetts, Med Ctr, Program Mol Med, Worcester, MA 01605 USA
[2] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
[3] Univ Vermont, Dept Med, Immunobiol Program, Burlington, VT 05405 USA
[4] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[5] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
关键词
TUMOR-NECROSIS-FACTOR; A-INDUCED HEPATITIS; SIGNAL-TRANSDUCTION PATHWAY; NECROTIC CELL-DEATH; CONCANAVALIN-A; IN-VIVO; LIVER-INJURY; INDUCED APOPTOSIS; INDUCED ACTIVATION; CRUCIAL ROLE;
D O I
10.1016/j.cell.2008.11.017
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:249 / 260
页数:12
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