Gadd45β promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling
Gadd45β promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling
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DOI：
10.1172/jci33913
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Franzosol, Guido
中科院分区：
文献类型：
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作者：
Papa, Salvatore;Zazzeroni, Francesca;Franzosol, Guido
在肝脏中，TNF受体（TNFRs）下游诱导JNK级联反应，以应对炎症、微生物和毒性挑战。JNK的持续激活会触发程序性细胞死亡（PCD），而在这些挑战中肝细胞的存活需要诱导nf - κ B通路，该通路通过上调靶基因来对抗这种激活。因此，JNK活性的调节对于肝脏对tnfr介导的挑战的反应至关重要。然而，这种调制的基础是未知的。在这里，我们研究了NF-kappa B靶点Gadd45b在部分肝切除术后肝再生过程中对肝细胞命运的调节作用。我们产生了Gadd45b（-/-）小鼠，发现它们在肝脏再生过程中表现出肝细胞增殖减少和PCD增加。值得注意的是，与对照组动物相比，部分肝切除术后Gadd45b（-/-）小鼠肝脏中JNK活性显著增加并持续。此外，施加jnk2缺失突变，降低JNK活性，完全恢复了Gadd45b（-/-）小鼠的再生反应。有趣的是，在tnfr介导的免疫攻击后，Gadd45 β消融不影响肝毒性JNK信号传导，这表明在不同tnfr介导的攻击中激活的JNK抑制的诱导肝程序具有特异性。这些数据为肝脏再生过程中JNK的抑制提供了基础，并确定了Gadd45 β是肝脏疾病的潜在治疗靶点。
In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in response to inflammatory, microbial, and toxic challenges. Sustained activation of JNK triggers programmed cell death (PCD), and hepatocyte survival during these challenges requires induction of the NF-kappa B pathway, which antagonizes this activation by upregulating target genes. Thus, modulation of JNK activity is crucial to the liver response to TNFR-mediated challenge. The basis for this modulation, however, is unknown. Here, we investigated the role of the NF-kappa B target Gadd45b in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b(-/-) mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in fivers of Gadd45b(-/-) mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b(-/-) mice. Interestingly, Gadd45 beta ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45 beta as a potential therapeutic target in liver diseases.