Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis.
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 (DeltaDD) 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 (FasDeltaDD) in their livers were completely protected against apoptosis and survived fulminant hepatitis. In T-cell-dependent concanavalin A-induced autoimmune hepatitis, FasDeltaDD antagonist expression prevented hepatocyte damage and mouse death. Finally, TNFR1DeltaDD effectively protected mice against LPS-induced septic shock. In conclusion, such DeltaDD-decoy receptors act as dominant-negative receptors exerting local inhibition, while avoiding systemic neutralization of apoptosis ligands, and might have therapeutic potential in hepatitis.
Descamps
Delphyne
D
CNRS UMR 8121 Vectorologie et Transfert de Gènes, Institut Gustave Roussy, Villejuif, France.
Vigant
Frédéric
F
Esselin
Stéphanie
S
Connault
Elisabeth
E
Opolon
Paule
P
Perricaudet
Michel
M
Benihoud
Karim
K
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein; D005260:Female; D015870:Gene Expression; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012313:RNA / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D012313:RNA