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Journal of Lipid Research, Vol. 45, 99-105, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology
* Department of Biochemistry and Molecular Biology, University of the Basque Country, P.O. Box 644, 48080 Bilbao, Spain
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
1 To whom correspondence should be addressed. e-mail: gbpgomua{at}lg.ehu.es
It was reported previously that ceramide-1-phosphate (Cer-1-P) is mitogenic for fibroblasts (Gómez-Muñoz, A., P. A. Duffy, A. Martin, L. O'Brien, H-S. Byun, R. Bittman, and D. N. Brindley. 1995. Mol. Pharmacol. 47: 883–889; Gómez-Muñoz, A., L. M. Frago, L. Alvarez, and I. Varela-Nieto. 1997. Biochem. J. 325: 435–440). We now show that Cer-1-P prevents cell death in bone-marrow-derived macrophages (BMDMs) after withdrawal of macrophage colony-stimulating factor (M-CSF). Removal of M-CSF is known to induce apoptosis in these cells. Cer-1-P blocked activation of the caspase-9/caspase-3 pathway and prevented DNA fragmentation, indicating that the enhancement of cell survival was due to inhibition of apoptosis. M-CSF deprivation resulted in activation of acid sphingomyelinase (A-SMase), increased ceramide levels, and a decrease in intracellular Cer-1-P. Exogenously added Cer-1-P inhibited A-SMase in intact BMDMs at concentrations that also prevented apoptosis. Cer-1-P also inhibited A-SMase in cell homogenates, suggesting a possible direct physical interaction of Cer-1-P with the enzyme.
In conclusion, these data demonstrate that Cer-1-P blocks apoptosis in BMDMs through inhibition of A-SMase, thereby reducing ceramide generation. This adds a new dimension to the understanding of the metabolic interrelationship of ceramides and Cer-1-P, and shows how altering the balance of intracellular levels of these mediators can affect cell survival.
Abbreviations: A-SMase, acid sphingomyelinase; BMDMs, bone marrow-derived macrophages; C2-, acetyl; C8-, octanoyl; Cer-1-P, ceramide-1-phosphate; ERK, extracellular-regulated kinase; MAPK, mitogen-activated protein kinase; M-CSF, macrophage colony-stimulating factor; MTS, [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium, inner salt]; Sph-1-P, sphingosine-1-phosphate
Supplementary key words sphingosine-1-phosphate • caspases • cell survival
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