Cycloserine and threo-dihydrosphingosine inhibit TNF-alpha-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-alpha signaling.
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.
Meyer
Sybille G E
SG
Institut für Physiologische Chemie, Universitätsklinikum Essen, Hufelandstrasse 55, D-45147 Essen, Germany. sybille.meyer@uni-essen.de
de Groot
Herbert
H
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003523:Cycloserine / Q000494:pharmacology*; D004336:Drug Antagonism; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002518:Ceramides; D014409:Tumor Necrosis Factor-alpha; C458141:erythro-dihydrosphingosine; D003523:Cycloserine; D010088:Oxidoreductases; C473786:dihydroceramide synthase; C108138:dihydroceramide desaturase; D013110:Sphingosine; C005682:safingol