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Expression of non‐signaling membrane‐anchored death receptors protects murine livers in different models of hepatitis
Author(s) -
Descamps Delphyne,
Vigant Frédéric,
Esselin Stéphanie,
Connault Elisabeth,
Opolon Paule,
Perricaudet Michel,
Benihoud Karim
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21257
Subject(s) - receptor , programmed cell death , biology , apoptosis , immunology , medicine , cancer research , biochemistry
Fas and tumor necrosis factor receptor 1 (TNFR1) are death receptors involved in various diseases such as hepatitis, sepsis, or graft rejection. Neutralizing antibodies to death ligands or soluble death receptors can inhibit cell death; however, they induce side effects because of their systemic actions. To specifically block death signaling to target cells, we created death domain–deficient (ΔDD) membrane‐anchored receptors, delivered to the liver by either recombinant adenovirus or hydrodynamic pressure of nonviral recombinant plasmids. In anti‐Fas antibody‐induced fulminant hepatitis, mice expressing recombinant Fas‐decoy receptors (FasΔDD) in their livers were completely protected against apoptosis and survived fulminant hepatitis. In T‐cell–dependent concanavalin A–induced autoimmune hepatitis, FasΔDD antagonist expression prevented hepatocyte damage and mouse death. Finally, TNFR1ΔDD effectively protected mice against LPS‐induced septic shock. In conclusion , such ΔDD‐decoy receptors act as dominant‐negative receptors exerting local inhibition, while avoiding systemic neutralization of apoptosis ligands, and might have therapeutic potential in hepatitis. (H EPATOLOGY 2006;44:399–409.)