Cycloserine and threo-dihydrosphingosine inhibit TNF-alpha-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-alpha signaling |
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Authors: | Meyer Sybille G E de Groot Herbert |
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Institution: | Institut für Physiologische Chemie, Universit?tsklinikum Essen, Hufelandstrasse 55, D-45147 Essen, Germany. sybille.meyer@uni-essen.de |
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Abstract: | Measuring the cell death induced by tumor necrosis factor (TNF-alpha) in L929 cells, we discovered for the first time that L-cycloserine, an established inhibitor of serine palmitoyltransferase, as well as DL-threo-dihydrosphingosine (threo-DHS, threo-sphinganine) significantly protected against TNF-alpha-induced cytotoxicity. Under the same conditions sphingosine and DL-erythro-dihydrosphingosine (erythro-DHS) did not change TNF-alpha-induced cytotoxicity, thus underlining the specificity of threo-DHS. In serine-labeled cells, newly (de novo) synthetized labeled ceramide was significantly diminished by threo-DHS alone or together with TNF-alpha, which makes the (dihydro) ceramide synthase the likely target of threo-DHS. These results suggest the decisive role of ceramide de novo synthesis in TNF signaling. |
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