Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system

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Science  27 Mar 1992:
Vol. 255, Issue 5052, pp. 1715-1718
DOI: 10.1126/science.1313189


The mechanism of tumor necrosis factor (TNF)-alpha signaling is unknown. TNF-alpha signaling may involve sphingomyelin hydrolysis to ceramide by a sphingomyelinase and stimulation of a ceramide-activated protein kinase. In a cell-free system, TNF-alpha induced a rapid reduction in membrane sphingomyelin content and a quantitative elevation in ceramide concentrations. Ceramide-activated protein kinase activity also increased. Kinase activation was mimicked by addition of sphingomyelinase but not by phospholipases A2, C, or D. Reconstitution of this cascade in a cell-free system demonstrates tight coupling to the receptor, suggesting this is a signal transduction pathway for TNF-alpha.

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