INHIBITION OF CERAMIDE-INDUCED APOPTOSIS BY BCL-2

Ceramide, a long chain sphingolipid that is generated intracellularly upon hydrolysis of membrane-associated sphingomyelin, has recently bee n implicated as a second messenger-like molecule that is produced dist al to ligation of the tumour necrosis factor receptor type 1 (TNFR1), as well as the related Fas (CD95/Apo-1) molecule, It is well establish ed that ligation of TNFR1 or Fas leads to apoptosis in most cases. Fur thermore, it has also recently been demonstrated that exposure to cell -permeable synthetic ceramides can result in apoptosis in many cases. These and other observations have led to the hypothesis th at accumula tion of intracellular ceramide may be a common element of several path ways that result in apoptosis. Here we show that exposure to synthetic ceramides triggers apoptosis in the human T lymphoblastoid cell lines , CEM and Jurkat, and that overexpression of the apoptosis-repressor p rotein, Bcl-2, renders these cells resistant to the apoptosis-inducing effects of ceramide, as well as to several other stimuli. Since expos ure to ceramides can result in either cell proliferation, differentiat ion, cycle arrest, or death, the level of Bcl-2 expression in a cell m ay be an important factor in determining the outcome of signals that r esult in intracellular generation of this sphingolipid.