Nitric oxide inhibits tumor necrosis factor-alpha-induced apoptosis by reducing the generation of ceramide.
Apoptosis triggered by death receptors proceeds after defined signal-transduction pathways. Whether signaling at the receptor level is regulated by intracellular messengers is still unknown. We have investigated the role of two messengers, ceramide and nitric oxide (NO), on the apoptotic pathway activated in human monocytic U937 cells by tumor necrosis factor-alpha (TNF-alpha) working at its p55 receptor. Two transduction events, the receptor recruitment of the adapter protein, TRADD, and the activation of the initiator caspase, caspase 8, were investigated. When administered alone, neither of the messengers had any effect on these events. In combination with TNF-alpha, however, ceramide potentiated, whereas NO inhibited, TNF-alpha-induced TRADD recruitment and caspase 8 activity. The effect of NO, which was cGMP-dependent, was due to inhibition of the TNF-alpha-induced generation of ceramide. Our results identify a mechanism of regulation of a signal-transduction pathway activated by death receptors.
De Nadai
C
C
Department of Neuroscience, DIBIT-H San Raffaele Institute, and Consiglio Nazionale delle Ricerche, Centre of Cellular and Molecular Pharmacology, 20132 Milan, Italy.
Sestili
P
P
Cantoni
O
O
Lièvremont
J P
JP
Sciorati
C
C
Barsacchi
R
R
Moncada
S
S
Meldolesi
J
J
Clementi
E
E
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D026423:S-Nitroso-N-Acetylpenicillamine; D015290:Second Messenger Systems; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D020298:U937 Cells
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D015703:Antigens, CD; D002518:Ceramides; D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011506:Proteins; D011810:Quinoxalines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D010396:Penicillamine; D006152:Cyclic GMP; D013110:Sphingosine