title: Protection against Fas-mediated and tumor necrosis factor receptor 1-mediated liver injury by blockade of FADD without loss of nuclear factor-kappaB activation.
abstract: OBJECTIVE
  To investigate the role of FADD (Fas-associated protein with death domain) in Fas and tumor necrosis factor receptor 1 (TNFR1)-mediated hepatic injury and inflammatory response in vivo.
  
  
  BACKGROUND
  Fas and TNFR1 are cell surface molecules that trigger apoptosis or inflammation on engagement by a specific ligand or antibody. FADD is recruited to the cytoplasmic domain of these receptors on their activation and works as a common mediator to induce apoptosis. It is known that a blockade of FADD can inhibit apoptosis mediated by Fas or TNFR1 in vitro. However, it is not known whether the blockade can prevent organ injury and whether the inflammatory cascade is affected in vivo.
  
  
  METHODS
  A FADD deletion mutant lacking the death effector domain was introduced into mice by transduction with an adenovirus vector, and the effect of this FADD dominant negative mutant was examined in several liver injury models.
  
  
  RESULTS
  Hepatic injury induced by anti-Fas monoclonal antibody or tumor necrosis factor (TNF)-alpha plus D-galactosamine was markedly ameliorated by the FADD dominant negative transduction, which abrogated the death rate. Further, the FADD dominant negative transduction efficiently blocked T cell- mediated concanavalin A-induced hepatitis while not affecting TNF-alpha production or TNF-alpha-induced nuclear factor-kappaB activation in the liver.
  
  
  CONCLUSIONS
  These results provide the basis for a novel therapeutic modality in which an unfavorable apoptotic process can be inhibited without affecting a favorable response for liver regeneration; this would be relevant to the clinical treatment of acute and chronic liver diseases as well as to some inflammatory disorders with hypercytokinemia, such as sepsis.
authors.affiliation: Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba Science City, Japan. seinok@md.tsukuba.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Seino
authors.forename: Y
authors.initials: Y
authors.lastname: Setoguchi
authors.forename: T
authors.initials: T
authors.lastname: Ogino
authors.forename: N
authors.initials: N
authors.lastname: Kayagaki
authors.forename: H
authors.initials: H
authors.lastname: Akiba
authors.forename: H
authors.initials: H
authors.lastname: Nakano
authors.forename: H
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Takada
authors.forename: K
authors.initials: K
authors.lastname: Yuzawa
authors.forename: T
authors.initials: T
authors.lastname: Todoroki
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuchi
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: K
authors.initials: K
authors.lastname: Fukao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003208:Concanavalin A; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005688:Galactosamine / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006505:Hepatitis / Q000209:etiology / Q000503:physiopathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D002352:Carrier Proteins; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D005688:Galactosamine