Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 97 (10): 5480-5485

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

Céline De Nadai*, Piero Sestili{dagger}, Orazio Cantoni{dagger}, Jean-Philippe Lièvremont*, Clara Sciorati*, Rico Barsacchi*, Salvador Moncada{ddagger}, Jacopo Meldolesi*, and Emilio Clementi*,§,¶

*Department of Neuroscience, DIBIT-H San Raffaele Institute, and Consiglio Nazionale delle Ricerche, Centre of Cellular and Molecular Pharmacology, 20132 Milan, Italy; {dagger}Institute of Pharmacology, University of Urbino, 61029, Italy; {ddagger}The Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom; and §Department of Pharmaco-Biology, University of Calabria, 87036 Rende, Italy

Contributed by Salvador Moncada

Accepted for publication February 11, 2000.

Abstract: 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-α (TNF-α) 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-α, however, ceramide potentiated, whereas NO inhibited, TNF-α-induced TRADD recruitment and caspase 8 activity. The effect of NO, which was cGMP-dependent, was due to inhibition of the TNF-α-induced generation of ceramide. Our results identify a mechanism of regulation of a signal-transduction pathway activated by death receptors.

To whom reprint requests should be addressed at: DIBIT-H San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. E-mail: clementi.emilio{at}hsr.it.

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.070062397.

Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.070062397

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Biological Roles of Acid and Neutral Sphingomyelinases and Their Regulation by Nitric Oxide.
C. Perrotta and E. Clementi (2010)
Physiology 25, 64-71
   Abstract »    Full Text »    PDF »
Nitric Oxide Signaling Is Disrupted in the Yeast Model for Batten Disease.
N. S. Osorio, A. Carvalho, A. J. Almeida, S. Padilla-Lopez, C. Leao, J. Laranjinha, P. Ludovico, D. A. Pearce, and F. Rodrigues (2007)
Mol. Biol. Cell 18, 2755-2767
   Abstract »    Full Text »    PDF »
Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell-Mediated Apoptosis, Uptake, and Cross-Presentation.
J. Huang, T. Tatsumi, E. Pizzoferrato, N. Vujanovic, and W. J. Storkus (2005)
Cancer Res. 65, 8461-8470
   Abstract »    Full Text »    PDF »
Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals.
E. Nisoli, S. Falcone, C. Tonello, V. Cozzi, L. Palomba, M. Fiorani, A. Pisconti, S. Brunelli, A. Cardile, M. Francolini, et al. (2004)
PNAS 101, 16507-16512
   Abstract »    Full Text »    PDF »
D-4F, an Apolipoprotein A-I Mimetic Peptide, Inhibits the Inflammatory Response Induced by Influenza A Infection of Human Type II Pneumocytes.
B. J. Van Lenten, A. C. Wagner, M. Navab, G.M. Anantharamaiah, E. K.-W. Hui, D. P. Nayak, and A. M. Fogelman (2004)
Circulation 110, 3252-3258
   Abstract »    Full Text »    PDF »
Induction of Endothelial Nitric Oxide Synthase Expression by Melanoma Sensitizes Endothelial Cells to Tumor Necrosis Factor-Driven Cytotoxicity.
S. Mocellin, M. Provenzano, C. R. Rossi, P. Pilati, R. Scalerta, M. Lise, and D. Nitti (2004)
Clin. Cancer Res. 10, 6879-6886
   Abstract »    Full Text »    PDF »
Activation of Acid Sphingomyelinase and Its Inhibition by the Nitric Oxide/Cyclic Guanosine 3',5'-Monophosphate Pathway: Key Events in Escherichia coli-Elicited Apoptosis of Dendritic Cells.
S. Falcone, C. Perrotta, C. De Palma, A. Pisconti, C. Sciorati, A. Capobianco, P. Rovere-Querini, A. A. Manfredi, and E. Clementi (2004)
J. Immunol. 173, 4452-4463
   Abstract »    Full Text »    PDF »
Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases.
Y. C. Boo and H. Jo (2003)
Am J Physiol Cell Physiol 285, C499-C508
   Abstract »    Full Text »    PDF »
Screening for Nitric Oxide-Dependent Protein-Protein Interactions.
A. Matsumoto, K. E. Comatas, L. Liu, and J. S. Stamler (2003)
Science 301, 657-661
   Abstract »    Full Text »    PDF »
Plasmodium falciparum-Infected Erythrocyte Adhesion Induces Caspase Activation and Apoptosis in Human Endothelial Cells.
P. Pino, I. Vouldoukis, J. P. Kolb, N. Mahmoudi, I. Desportes-Livage, F. Bricaire, M. Danis, B. Dugas, and D. Mazier (2003)
The Journal of Infectious Disease 187, 1283-1290
   Abstract »    Full Text »    PDF »
Activation of Endothelial Nitric-Oxide Synthase by Tumor Necrosis Factor-alpha : A Novel Pathway Involving Sequential Activation of Neutral Sphingomyelinase, Phosphatidylinositol-3' kinase, and Akt.
R. Barsacchi, C. Perrotta, S. Bulotta, S. Moncada, N. Borgese, and E. Clementi (2003)
Mol. Pharmacol. 63, 886-895
   Abstract »    Full Text »    PDF »
Mitochondrial Biogenesis in Mammals: The Role of Endogenous Nitric Oxide.
E. Nisoli, E. Clementi, C. Paolucci, V. Cozzi, C. Tonello, C. Sciorati, R. Bracale, A. Valerio, M. Francolini, S. Moncada, et al. (2003)
Science 299, 896-899
   Abstract »    Full Text »    PDF »
Synergism of nitric oxide and maturation signals on human dendritic cells occurs through a cyclic GMP-dependent pathway.
C. Paolucci, S. E. Burastero, P. Rovere-Querini, C. De Palma, S. Falcone, C. Perrotta, A. Capobianco, A. A. Manfredi, and E. Clementi (2003)
J. Leukoc. Biol. 73, 253-262
   Abstract »    Full Text »    PDF »
Caspase-8-mediated BID Cleavage and Release of Mitochondrial Cytochrome c during Nomega -Hydroxy-L-arginine-induced Apoptosis in MDA-MB-468 Cells. ANTAGONISTIC EFFECTS OF L-ORNITHINE.
R. Singh, S. Pervin, and G. Chaudhuri (2002)
J. Biol. Chem. 277, 37630-37636
   Abstract »    Full Text »    PDF »
Relationships between caveolae and eNOS: everything in proximity and the proximity of everything.
M. S. Goligorsky, H. Li, S. Brodsky, and J. Chen (2002)
Am J Physiol Renal Physiol 283, F1-F10
   Abstract »    Full Text »    PDF »
Disruption of Inducible Nitric Oxide Synthase Improves {beta}-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy.
H. Funakoshi, T. Kubota, N. Kawamura, Y. Machida, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita (2002)
Circ. Res. 90, 959-965
   Abstract »    Full Text »    PDF »
Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II.
A. P. Gobert, Y. Cheng, J.-Y. Wang, J.-L. Boucher, R. K. Iyer, S. D. Cederbaum, R. A. Casero Jr., J. C. Newton, and K. T. Wilson (2002)
J. Immunol. 168, 4692-4700
   Abstract »    Full Text »    PDF »
O2-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Against D-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays.
J. Liu, J. E. Saavedra, T. Lu, J.-G. Song, J. Clark, M. P. Waalkes, and L. K. Keefer (2002)
J. Pharmacol. Exp. Ther. 300, 18-25
   Abstract »    Full Text »    PDF »
Role of Iron in Tumor Cell Protection from the Pro-Apoptotic Effect of Nitric Oxide.
F. Feger, H. Ferry-Dumazet, M. M. Matsuda, J. Bordenave, M. Dupouy, A. K. Nussler, M. Arock, L. Devevey, J. Nafziger, J.-J. Guillosson, et al. (2001)
Cancer Res. 61, 5289-5294
   Abstract »    Full Text »    PDF »
Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase.
S. Shiva, P. S. Brookes, R. P. Patel, P. G. Anderson, and V. M. Darley-Usmar (2001)
PNAS 98, 7212-7217
   Abstract »    Full Text »    PDF »
Activation of the Endothelial Nitric-oxide Synthase by Tumor Necrosis Factor-alpha . A NOVEL FEEDBACK MECHANISM REGULATING CELL DEATH.
S. Bulotta, R. Barsacchi, D. Rotiroti, N. Borgese, and E. Clementi (2001)
J. Biol. Chem. 276, 6529-6536
   Abstract »    Full Text »    PDF »
Activation of the Endothelial Nitric-oxide Synthase by Tumor Necrosis Factor-alpha . A NOVEL FEEDBACK MECHANISM REGULATING CELL DEATH.
S. Bulotta, R. Barsacchi, D. Rotiroti, N. Borgese, and E. Clementi (2001)
J. Biol. Chem. 276, 6529-6536
   Abstract »    Full Text »    PDF »
Natural Ceramide Reverses Fas Resistance of Acid Sphingomyelinase-/- Hepatocytes.
F. Paris, H. Grassme, A. Cremesti, J. Zager, Y. Fong, A. Haimovitz-Friedman, Z. Fuks, E. Gulbins, and R. Kolesnick (2001)
J. Biol. Chem. 276, 8297-8305
   Abstract »    Full Text »    PDF »
S-Nitrosylation of mitochondrial caspases.
J. B. Mannick, C. Schonhoff, N. Papeta, P. Ghafourifar, M. Szibor, K. Fang, and B. Gaston (2001)
J. Cell Biol. 154, 1111-1116
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882