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Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death
G S Dbaibo1, W El-Assaad, A Krikorian
1Department of Pediatrics, American University of Beirut, Lebanon. gdbaibo@aub.edu.lb
FEBS Letters
|August 22, 2001
Summary
Blocking de novo ceramide synthesis and using glutathione to inhibit sphingomyelin hydrolysis significantly reduces ceramide accumulation and cell death, revealing complex cytokine signaling pathways.
Area of Science:
- Cellular Biology
- Biochemistry
- Immunology
Background:
- Ceramide accumulation is linked to cell death.
- Ceramides can be synthesized de novo or generated via sphingomyelin hydrolysis.
- Tumor necrosis factor alpha (TNF-α) induces cell death.
Purpose of the Study:
- To investigate the roles of de novo synthesis and sphingomyelin hydrolysis in TNF-α-induced ceramide accumulation and cell death.
- To determine the combined effect of inhibiting both ceramide generation pathways.
Main Methods:
- Blocking de novo ceramide synthesis.
- Pre-treating cells with glutathione to inhibit neutral sphingomyelinase.
- Measuring ceramide accumulation and cell death.
- Utilizing TNF-α as a stimulus.
Main Results:
- Inhibiting de novo ceramide synthesis significantly reduced ceramide accumulation and cell death.
- Glutathione pre-treatment inhibited early ceramide accumulation and attenuated cell death.
- Simultaneous inhibition of both pathways nearly abolished ceramide accumulation and cell death.
- Both pathways are stimulated by TNF-α.
Conclusions:
- Both de novo synthesis and sphingomyelin hydrolysis contribute to TNF-α-induced ceramide generation.
- Targeting both pathways offers a potent strategy to prevent ceramide-mediated cell death.
- Ceramide generation in response to cytokines is complex and involves multiple pathways.