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Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2006 Aug; Vol. 44 (2), pp. 399-409. - Publication Year :
- 2006
-
Abstract
- 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.
- Subjects :
- Adaptor Proteins, Signal Transducing biosynthesis
Animals
Blotting, Western
Disease Models, Animal
Fas-Associated Death Domain Protein
Female
Hepatitis pathology
Hepatitis prevention & control
Membrane Glycoproteins metabolism
Mice
Mice, Inbred BALB C
Reverse Transcriptase Polymerase Chain Reaction
Adaptor Proteins, Signal Transducing genetics
Apoptosis physiology
Gene Expression
Hepatitis metabolism
RNA genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0270-9139
- Volume :
- 44
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 16871589
- Full Text :
- https://doi.org/10.1002/hep.21257