Ceramide generation by two distinct pathways in tumor necrosis factor α‐induced cell death

• Published in: FEBS letters 2001-08, Vol.503 (1), p.7-12
• Main Authors: Dbaibo, Ghassan S, El-Assaad, Wissal, Krikorian, Armand, Liu, Bin, Diab, Karim, Idriss, Nadine Z, El-Sabban, Marwan, Driscoll, Timothy A, Perry, David K, Hannun, Yusuf A
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - physiology; Cell death; Ceramide; Ceramide synthase; Ceramides - biosynthesis; FB1, fumonisin B1; Glutathione - metabolism; GSH, glutathione; Humans; N-SMase, neutral sphingomyelinase; ROI, reactive oxygen intermediate; Sphingomyelinase; TNFα, tumor necrosis factor α; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(01)02625-4

Ceramide accumulation in the cell can occur from either hydrolysis of sphingomyelin or by de novo synthesis. In this study, we found that blocking de novo ceramide synthesis significantly inhibits ceramide accumulation and subsequent cell death in response to tumor necrosis factor α. When cells were pre‐treated with glutathione, a proposed cellular regulator of neutral sphingomyelinase, inhibition of ceramide accumulation at early time points was achieved with attenuation of cell death. Inhibition of both pathways achieved near‐complete inhibition of ceramide accumulation and cell death indicating that both pathways of ceramide generation are stimulated. This illustrates the complexity of ceramide generation in cytokine action.