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

C De Nadai1, P Sestili, O Cantoni

  • 1Department of Neuroscience, DIBIT-H San Raffaele Institute, and Consiglio Nazionale delle Ricerche, Centre of Cellular and Molecular Pharmacology, 20132 Milan, Italy.

Proceedings of the National Academy of Sciences of the United States of America
|May 3, 2000
PubMed

Insights

This study reveals how ceramide enhances and nitric oxide (NO) inhibits tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis signaling. NO achieves this by blocking ceramide generation, uncovering a novel regulatory mechanism for death receptor pathways.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Immunology

Background:

  • Apoptosis, or programmed cell death, is initiated by death receptors through defined signaling pathways.
  • The regulation of these pathways by intracellular messengers at the receptor level remains largely unexplored.
  • Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine that triggers apoptosis via its p55 receptor.

Purpose of the Study:

  • To investigate the role of ceramide and nitric oxide (NO) as intracellular messengers in TNF-alpha-induced apoptosis.
  • To determine how these messengers affect key signal transduction events: TRADD recruitment and caspase 8 activation.

Main Methods:

  • Utilized human monocytic U937 cells treated with TNF-alpha.
  • Assessed the impact of ceramide and NO, alone and in combination with TNF-alpha, on TRADD recruitment and caspase 8 activation.
  • Investigated the mechanism of NO's action, including its cGMP dependence and effect on ceramide generation.

Main Results:

  • Ceramide potentiated TNF-alpha-induced TRADD recruitment and caspase 8 activity.
  • Nitric oxide (NO) inhibited TNF-alpha-induced TRADD recruitment and caspase 8 activity.
  • NO's inhibitory effect was cGMP-dependent and mediated by blocking TNF-alpha-induced ceramide generation.

Conclusions:

  • Ceramide and NO act as critical regulators of the TNF-alpha-mediated apoptotic signaling pathway.
  • NO inhibits apoptosis by suppressing the generation of ceramide, a pro-apoptotic messenger.
  • These findings elucidate a novel regulatory mechanism controlling signal transduction initiated by death receptors.

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