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Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.

ABSTRACT: 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 hepatocyte-specific Bid deficient mice (hBid(-/-)). Acute liver injury was induced by Fas-activating antibody (Jo2) in a time-course study.In contrast to controls, nearly all Jo2 injected hBid(-/-) 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 non-canonical interleukin-1? 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 non-canonical interleukin-1? 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.

SUBMITTER: Lazic M

PROVIDER: S-EPMC4712949 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.

Lazic Milos M Eguchi Akiko A Berk Michael P MP Povero Davide D Papouchado Bettina B Mulya Anny A Johnson Casey D CD Feldstein Ariel E AE

Journal of hepatology 20140327 1

<h4>Background & aims</h4>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.<h4>Methods</h4>We generated hepatocyte-s ...[more]

PMID: 24681344

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Project description:Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion--a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid(?hep)) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid(?hep) mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid(?hep) animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-?, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid(?hep) mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid(?hep) mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid(?hep) and Bid(flo/flo) mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

Dataset Information

Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.

Publications

Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.

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