Abstract
Activation of the cysteine protease caspases, which are homologous to the product of Caenorhabditis elegans cell-death gene ced 3, is required to mediate APO-1/Fas-induced apoptosis. We report here that nitric oxide (NO) released by exogenous NO donors, as well as NO endogenously derived by transfection with the inducible NO synthase, substantially suppresses APO-1/Fas-triggered cell death of Jurkat cells. The inhibitory NO effect was independent of cGMP, because 8-bromo-cGMP did not influence APO-1/Fas-mediated apoptosis. In contrast, NO interferes with the APO-1/Fas-induced stimulation of caspases. NO inhibits the proteolytic cleavage of caspase-3 (CPP32) into its active subunits, thereby suppressing caspase-3 activity. In addition, NO potently inhibits apoptosis induction by overexpresssion of the death domain protein FADD or the immediate downstream target caspase-8. These results suggest that NO modulates the proteolytic cascade upstream of caspase-3. Indeed, NO specifically S-nitrosylates caspase-8 and caspase-1 and thereby may prevent activation of the proteolytic cascade. The NO-mediated increase in the resistance toward induction of apoptosis may play a major role in mediating immune responses, as well as in the pathogenesis of autoimmune diseases.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Animals
-
Antibodies / pharmacology
-
Apoptosis*
-
Carrier Proteins / metabolism
-
Caspase 1
-
Caspase 3
-
Caspase 8
-
Caspase 9
-
Caspases*
-
Cycloheximide / pharmacology
-
Cysteine Endopeptidases / metabolism
-
Dactinomycin / pharmacology
-
Dose-Response Relationship, Drug
-
Fas-Associated Death Domain Protein
-
Glutathione / analogs & derivatives
-
Glutathione / pharmacology
-
Humans
-
Jurkat Cells
-
Mice
-
Nitric Oxide / metabolism
-
Nitric Oxide / pharmacology
-
Nitric Oxide / physiology*
-
Nitric Oxide Synthase / genetics
-
Nitric Oxide Synthase / metabolism
-
Nitric Oxide Synthase Type II
-
Nitroprusside / pharmacology
-
Nitroso Compounds / pharmacology
-
Penicillamine / analogs & derivatives
-
Penicillamine / pharmacology
-
Protein Synthesis Inhibitors / pharmacology
-
S-Nitrosoglutathione
-
Signal Transduction
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / metabolism
-
T-Lymphocytes / pathology*
-
fas Receptor / immunology
-
fas Receptor / physiology*
Substances
-
Adaptor Proteins, Signal Transducing
-
Antibodies
-
Carrier Proteins
-
FADD protein, human
-
Fadd protein, mouse
-
Fas-Associated Death Domain Protein
-
Nitroso Compounds
-
Protein Synthesis Inhibitors
-
S-nitro-N-acetylpenicillamine
-
fas Receptor
-
Nitroprusside
-
Dactinomycin
-
Nitric Oxide
-
S-Nitrosoglutathione
-
Cycloheximide
-
NOS2 protein, human
-
Nitric Oxide Synthase
-
Nitric Oxide Synthase Type II
-
Nos2 protein, mouse
-
CASP3 protein, human
-
CASP8 protein, human
-
CASP9 protein, human
-
Casp3 protein, mouse
-
Casp8 protein, mouse
-
Casp9 protein, mouse
-
Caspase 3
-
Caspase 8
-
Caspase 9
-
Caspases
-
Cysteine Endopeptidases
-
Caspase 1
-
Glutathione
-
Penicillamine