Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.
Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.
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DOI：
10.1016/j.jhep.2014.03.028
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发表时间：
2014-07
影响因子：
25.7
通讯作者：
Feldstein AE
中科院分区：
文献类型：
--
作者：
Lazic M;Eguchi A;Berk MP;Povero D;Papouchado B;Mulya A;Johnson CD;Feldstein AE
Fas死亡受体的激活导致多个器官，特别是肝脏的细胞凋亡，这一过程依赖于Bid的切割。注射抗Fas抗体的小鼠在急性肝功能衰竭后几个小时内死亡，伴随着大量的细胞凋亡和出血。我们的目的是研究细胞凋亡和炎症途径的交叉以及选择性肝细胞凋亡在体内Fas激活过程中的作用。我们产生了肝细胞特异性BID缺陷小鼠(hBid−/−)。用Fas激活抗体(Jo2)诱导大鼠急性肝损伤。与对照组相比，注射了hBid−/−的Jo2几乎全部存活。他们的肝脏表现出对肝细胞凋亡的完全保护作用，仅有极少量的局灶性出血改变，主要是非实质细胞的凋亡。肝细胞胞浆中没有线粒体细胞色素c的释放，也没有caspase3的激活。HBid−/−肝中由中性粒细胞和单核细胞组成的急性炎症灶明显增多，并伴随促炎症趋化因子和细胞因子的表达增加，这种方式依赖于非规范的IL-1β激活，并在没有caspase-3激活的情况下放大。此外，hBid−/−小鼠在单次注射Jo2 2周后，可完全保护肝细胞免受肝损伤，并清除浸润性细胞。肝细胞BID抑制是体内抵抗Fas激活致死效应的关键。Fas信号诱导肝细胞中非规范的IL-1β成熟的差异激活，在没有凋亡的Bid-线粒体环的情况下被放大。这些发现可能对与Fas激活相关的各种肝脏疾病具有重要的病理生理和治疗意义。
Activation of Fas death receptor results in apoptosis in multiple organs, particularly liver, in a process dependent on Bid cleavage. Mice injected with an anti-Fas antibody die within hours of acute liver failure associated with massive apoptosis and hemorrhage. Our aim was to investigate the crosstalk of apoptotic and inflammatory pathways and the contribution of selective hepatocellular apoptosis during in vivo Fas activation. We generated hepatocytes-specific Bid deficient mice (hBid−/−). Acute liver injury was induced by Fas-activating antibody (Jo2) in a time-course study. In contrast to controls, Jo2 injected hBid−/− nearly all survived. Their livers showed complete protection against hepatocellular apoptosis with minimal focal hemorrhagic changes and mainly non-parenchymal cell apoptosis. In agreement, the hepatocytes had no mitochondrial cytochrome c release in cytosol, or caspase 3 activation. hBid−/− livers showed marked increase in acute inflammatory foci composed of neutrophils and monocytes associated with the increased expression of proinflammatory chemokines and cytokines, in the manner dependent on noncanonical interleukin-1β activation and amplified in the absence of caspase-3 activation. In addition, hBid−/− mice were completely protected from hepatotoxicity and the infiltrated cells were cleared 2 weeks post single Jo2 injection. Hepatocyte Bid suppression is critical for the resistance to the lethal effects of Fas activation in vivo. Fas signaling induces differential activation of noncanonical interleukin-1β maturation, amplified in the absence of apoptotic Bid-mitochondrial loop, in hepatocytes. These findings may have important pathophysiological and therapeutic implications in a variety of liver disorders associated with Fas activation.