Milos Lazic1, Akiko Eguchi1, Michael P Berk2, Davide Povero1, Bettina Papouchado3, Anny Mulya2, Casey D Johnson1, Ariel E Feldstein4. 1. Department of Pediatrics, University of California - San Diego, La Jolla, CA, United States. 2. Department of Cell Biology, Cleveland Clinic, Cleveland, OH, United States. 3. Department of Pathology, University of California - San Diego, La Jolla, CA, United States. 4. Department of Pediatrics, University of California - San Diego, La Jolla, CA, United States; Department of Cell Biology, Cleveland Clinic, Cleveland, OH, United States. Electronic address: afeldstein@ucsd.edu.
Abstract
BACKGROUND & AIMS: 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. METHODS: We generated hepatocyte-specific Bid deficient mice (hBid(-/-)). Acute liver injury was induced by Fas-activating antibody (Jo2) in a time-course study. RESULTS: 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-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. CONCLUSIONS: 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-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.
BACKGROUND & AIMS: 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. METHODS: We generated hepatocyte-specific Bid deficient mice (hBid(-/-)). Acute liver injury was induced by Fas-activating antibody (Jo2) in a time-course study. RESULTS: 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-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. CONCLUSIONS: 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-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.
Authors: Sean P Cullen; Conor M Henry; Conor J Kearney; Susan E Logue; Maria Feoktistova; Graham A Tynan; Ed C Lavelle; Martin Leverkus; Seamus J Martin Journal: Mol Cell Date: 2013-02-21 Impact factor: 17.970
Authors: Christian Liedtke; Jörg-Martin Bangen; Julia Freimuth; Naiara Beraza; Daniela Lambertz; Francisco J Cubero; Maximilian Hatting; Karlin R Karlmark; Konrad L Streetz; Gabriele A Krombach; Frank Tacke; Nikolaus Gassler; Dieter Riethmacher; Christian Trautwein Journal: Gastroenterology Date: 2011-08-28 Impact factor: 22.682
Authors: A Wree; C D Johnson; J Font-Burgada; A Eguchi; D Povero; M Karin; A E Feldstein Journal: Cell Death Differ Date: 2015-04-24 Impact factor: 15.828