title: Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.
abstract: OBJECTIVE
  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.affiliation: Department of Pediatrics, University of California - San Diego, La Jolla, CA, United States.
authors.forename: Milos
authors.initials: M
authors.lastname: Lazic
authors.affiliation: Department of Pediatrics, University of California - San Diego, La Jolla, CA, United States.
authors.forename: Akiko
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Cell Biology, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Berk
authors.affiliation: Department of Pediatrics, University of California - San Diego, La Jolla, CA, United States.
authors.forename: Davide
authors.initials: D
authors.lastname: Povero
authors.affiliation: Department of Pathology, University of California - San Diego, La Jolla, CA, United States.
authors.forename: Bettina
authors.initials: B
authors.lastname: Papouchado
authors.affiliation: Department of Cell Biology, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Anny
authors.initials: A
authors.lastname: Mulya
authors.affiliation: Department of Pediatrics, University of California - San Diego, La Jolla, CA, United States.
authors.forename: Casey D
authors.initials: CD
authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000172:deficiency* / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; C491899:Fas protein, mouse; D020690:GTPase-Activating Proteins; D053583:Interleukin-1beta; C490620:Ralbp1 protein, mouse; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Acute liver failure; Crosstalk of inflammatory and apoptotic pathways; Fas-mediated hepatic apoptosis; Hepatoprotection; Inflammation; Non-canonical IL-1β maturation