SUPPRESSION OF CERAMIDE-MEDIATED PROGRAMMED CELL-DEATH BY SPHINGOSINE-1-PHOSPHATE

CERAMIDE is an important regulatory participant of programmed cell dea th (apoptosis) induced by tumour-necrosis factor (TNF)-alpha and Fas l igand, members of the TNF superfamily(1-6). Conversely, sphingosine an d sphingosine-1-phosphate, which are metabolites of ceramide, induce m itogenesis(7) and have been implicated as second messengers in cellula r proliferation induced by platelet-derived growth factor and serum(8, 9). Here we report that sphingosine-1-phosphate prevents the appearanc e of the key features of apoptosis, namely intranucleosomal DNA fragme ntation and morphological changes, which result from increased concent rations of ceramide. Furthermore, inhibition of ceramide-mediated apop tosis by activation of protein kinase C results from stimulation of sp hingosine kinase and the concomitant increase in intracellular sphingo sine-l-phosphate. Finally sphingosine-1-phosphate not only stimulates the extracellular signal-regulated kinase (ERK) pathway(10), it counte racts the ceramide-induced activation of stress-activated protein kina se (SAPK/JNK). Thus, the balance between the intracellular levels of c eramide and sphingosine-1-phosphate and their regulatory effects on di fferent family members of mitogen-activated protein kinases determines the fate of the cell.