Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

doi:10.1194/jlr.M300158-JLR200

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Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages

Antonio Gómez-Muñoz, Jennifer Y. Kong, Bill Salh, and Urs P. Steinbrecher

Biochemistry and Molecular Biology, University of the Basque Country, Bilbao, Bizkaia 48080

Corresponding Author: gbpgomua{at}lg.ehu.es

It was reported previously that ceramide-1-phosphate (Cer-1-P) is mitogenic for fibroblasts [A. Gómez-Muñoz, P.A. Duffy, A. Martin, L. O'Brien, H-S. Byun, R. Bittman, and D.N. Brindley. Mol. Pharmacol. 47, 883-889 (1995); A. Gómez-Muñoz, L.M. Frago, L. Alvarez, and I. Varela-Nieto. Biochem. J. 325, 435-440 (1997). We now show that Cer-1-P blocks cell death in bone-marrow derived macrophages (BMDM) incubated in the absence of macrophage-colony stimulating factor (M-CSF), a condition known to induce apoptosis in these cells. Cell death following M-CSF withdrawal was accompanied by activation of the caspase-9/caspase-3 pathway and DNA fragmentation, both of which were inhibited by Cer-1-P. M-CSF deprivation resulted in activation of acidic sphingomyelinase (A-SMase) and increased ceramide levels in the macrophages, and Cer-1-P completely blocked these effects. Cer-1-P inhibited A-SMase activity both in intact BMDM as well as in cell homogenates, suggesting a possible direct physical interaction of Cer-1-P with the enzyme. Increasing the intracellular concentration of ceramide by treatment of BMDM with N-acetyl-sphingosine (C2-ceramide) reversed the anti-apoptotic effect of Cer-1-P. In conclusion, the data presented here demonstrate that Cer-1-P blocks apoptosis in BMDM through inhibition of A-SMase and 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.

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