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

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. 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. The breakdown of sphingomyelin (SM) produces bioactive sphingolipid metabolites, some of which are believed to act as second messengers that control critical cellular functions. For example, N-deacylation of SM generates sphingosine phosphocholine, which is mitogenic for fibroblasts (1Berger A. Bittman R. Schmidt R.D. Spiegel S. Mol. Pharmacol. 1996; 50: 451-457PubMed Google Scholar). Stimulation of SMase activity produces ceramides, which can inhibit cell proliferation and are potent inducers of apoptosis (2Hannun Y.A. The sphingomyelin cycle and the second messenger function of ceramide.J. Biol. Chem. 1994; 269: 3125-3128Abstract Full Text PDF PubMed Google Scholar, 3Hannun Y.A. Functions of ceramide in coordinating cellular responses to stress.Science. 1996; 274: 1855-1859Crossref PubMed Scopus (1493) Google Scholar, 4Kolesnick R. Golde D.W. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling.Cell. 1994; 77: 325-328Abstract Full Text PDF PubMed Scopus (915) Google Scholar). Ceramides have been shown to regulate several protein kinases, including ceramide-activated protein kinase (5Zhang Y. Yao B. Delikat S. Bayoumi S. Lin X.H. Basu S. McGinley M. Chan-Hui P.Y. Lichenstein H. Kolesnick R. Kinase supressor of Ras is ceramide-activated protein kinase.Cell. 1997; 89: 63-72Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar, 6Yao B. Zhang Y. Delikat S. Mathias S. Basu S. Kolesnick R. Phosphorylation of Raf by ceramide-activated protein kinase.Nature. 1995; 378: 307-310Crossref PubMed Scopus (303) Google Scholar) and protein kinase C (7Lozano J. Berra E. Municio M.M. Diaz-Meco M.T. Dominguez I. Sanz L. Moscat J. Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase.J. Biol. Chem. 1994; 265: 19200-19202Abstract Full Text PDF Google Scholar), or protein phosphatases of the 2 A family (8Chalfant C.E. Rathman K. Pinkerman R.L. Wood R.E. Obeid L.M. Ogretmen B. Hannun Y.A. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells.J. Biol. Chem. 2002; 277: 12587-12595Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar). In addition, ceramides are potent inhibitors of phospholipase D, both in cultured cells (9Gómez-Muñoz A. Martin A. O'Brien L. Brindley D.N. Cell-permeable ceramides inhibit the stimulation of DNA synthesis and phospholipase D activity by phosphatidate and lysophosphatidate in rat fibroblasts.J. Biol. Chem. 1994; 269: 8937-8943Abstract Full Text PDF PubMed Google Scholar, 10Gómez-Muñoz A. Waggoner D.W. O'Brien L. Brindley D.N. Interaction of ceramides, sphingosine, and sphingosine 1-phosphate in regulating DNA synthesis and phospholipase D activity.J. Biol. Chem. 1995; 270: 26318-26325Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) and in cell-free systems (11Abousalham A. Liossis C. O'Brien L. Brindley D.N. Cell permeable ceramides prevent the activation of phospholipase D by ADP-ribosylation factor and Rho A.J. Biol. Chem. 1997; 272: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Ceramides can be degraded by ceramidases to sphingosine, and this, in turn, can be phosphorylated by sphingosine kinase to produce sphingosine-1-phosphate (Sph-1-P). Both sphingosine and Sph-1-P have been implicated in the regulation of cell proliferation and death (12Spiegel S. Olivera A. Carlson R.O. The role of sphingosine in cell growth regulation and transmembrane signaling.Adv. Lipid Res. 1993; 25: 105-127PubMed Google Scholar, 13Spiegel S. Milstien S. Sphingosine 1-phosphate, a key cell signaling molecule.J. Biol. Chem. 2002; 277: 25851-25854Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 14Payne S.G. Milstien S. Spiegel S. Sphingosine-1-phosphate: dual messenger functions.FEBS Lett. 2002; 531: 54-57Crossref PubMed Scopus (183) Google Scholar, 15Gómez-Muñoz A. Kong J. Salh B. Steinbrecher U. Sphingosine-1-phosphate inhibits sphingomyelinase and blocks apoptosis in macrophages.FEBS Lett. 2003; 539: 56-60Crossref PubMed Scopus (74) Google Scholar). Another important ceramide metabolite that can be generated through the action of ceramide kinase is ceramide-1-phosphate (Cer-1-P) (16Bajjalieh S.M. Martin T.F.J. Floor E. Synaptic vesicle ceramide kinase. A calcium-stimulated lipid kinase that copurifies with brain synaptic vesicles.J. Biol. Chem. 1989; 264: 14354-14360Abstract Full Text PDF PubMed Google Scholar, 17Sugiura M. Kono K. Liu H. Shimizugawa T. Minekura H. Spiegel S. Kohama T. Ceramide kinase, a novel lipid kinase.J. Biol. Chem. 2002; 277: 23294-23300Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). Boudker and Futerman (18Boudker O. Futerman A.H. Detection and characterization of ceramide-1-phosphate phosphatase activity in rat liver plasma membrane.J. Biol. Chem. 1993; 268: 22150-22155Abstract Full Text PDF PubMed Google Scholar) characterized a phosphatase that specifically hydrolyzes Cer-1-P in plasma membranes, suggesting that ceramide and Cer-1-P can be interconverted in cells. More recently, Riboni et al. (19Riboni L. Bassi R. Anelli V. Viani P. Metabolic formation of ceramide-1-phosphate in cerebellar granule cells: evidence for the phosphorylation of ceramide by different metabolic pathways.Neurochem. Res. 2002; 27: 711-716Crossref PubMed Scopus (24) Google Scholar) observed that Cer-1-P can also be produced from the recycling of sphingosine produced from ganglioside catabolism, and Rile et al. (20Rile G. Yatomi Y. Takafuta T. Ozaki Y. Ceramide 1-phosphate formation in neutrophils.Acta Haematol. 2003; 109: 76-83Crossref PubMed Scopus (36) Google Scholar) reported that Cer-1-P can be formed intracellularly in neutrophils. Critical biological functions have been attributed to Cer-1-P. We first found that short-chain acetyl (C2)- and octanoyl (C8)-Cer-1-P, as well as natural long-chain Cer-1-P, stimulated the incorporation of [3H]thymidine into DNA in fibroblasts, and that this action did not involve conversion of Cer-1-P to Sph-1-P (21Gómez-Muñoz A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar, 22Gómez-Muñoz A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar). More recently, it was found that Cer-1-P can be generated during the phagocytosis of antibody-coated erythrocytes through stimulation of SMase activity in neutrophils, and that it plays an important role in liposome fusion (23Hinkovska-Galcheva V.T. Boxer L.A. Mansfield P.J. Harsh D. Blackwood A. Shayman J.A. The formation of ceramide-1-phosphate during neutrophil phagocytosis and its role in liposome fusion.J. Biol. Chem. 1998; 273: 333203-333209Abstract Full Text Full Text PDF Scopus (115) Google Scholar). To date, little is known about the metabolic pathways that may be modulated by Cer-1-P. We observed that Cer-1-P, at concentrations within the micromolar range, did not affect phospholipase D (PLD), mitogen-activated protein kinase (MAPK), adenylyl cyclase, or Ca2+ mobilization in fibroblasts, and that it did not alter the expression of the early genes c-fos or c-myc (21Gómez-Muñoz A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar, 22Gómez-Muñoz A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar). Failure of C8-Cer-1-P to induce intracellular Ca2+ mobilization has been confirmed recently in neutrophils (20Rile G. Yatomi Y. Takafuta T. Ozaki Y. Ceramide 1-phosphate formation in neutrophils.Acta Haematol. 2003; 109: 76-83Crossref PubMed Scopus (36) Google Scholar). However, Gijsbers et al. (24Gijsbers S. Mannaerts G.P. Himpens B. Van Veldhoven P.P. N-acetyl-sphingenine-1-phosphate is a potent calcium mobilizing agent.FEBS Lett. 1999; 453: 269-272Crossref PubMed Scopus (25) Google Scholar) and Hogback et al. (25Hogback S. Leppimaki P. Rudnas B. Bjorklund S. Slotte J.P. Tornquist K. Ceramide 1-phosphate increases intracellular free calcium concentrations in thyroid FRTL-5 cells: evidence for an effect mediated by inositol 1,4,5-trisphosphate and intracellular sphingosine 1-phosphate.Biochem. J. 2003; 370: 111-119Crossref PubMed Scopus (40) Google Scholar) reported that C2-Cer-1-P caused fast and transient intracellular rises in Ca2+ in both calf pulmonary artery endothelial cells and thyroid FRTL-5 cells, respectively, an action that might be related to the mitogenic effect of C2-Cer-1-P. In recent studies, we found evidence of sphingomyelinase activation and ceramide generation in bone marrow-derived macrophages (BMDMs) induced to undergo apoptosis by growth factor withdrawal (26Hundal R.S. Gómez-Muñoz A. Salh B. Marotta A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis by ceramide generation thereby activation and Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). We also that inhibition of SMase activity with prevented apoptosis in indicating that in this of ceramides a role (26Hundal R.S. Gómez-Muñoz A. Salh B. Marotta A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis by ceramide generation thereby activation and Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the was to Cer-1-P inhibit cell death in In this we demonstrate that Cer-1-P inhibits apoptosis in macrophages and show that the Cer-1-P this effect inhibition of SMase thereby formation of Cer-1-P and and SM from was from sphingosine, and Sph-1-P from and SM from to from and to and 9 by and from by macrophages from of as J.A. D. R. G. S. Oxidized can induce macrophage DNA and to and Biol. 1999; PubMed Scopus Google Scholar). for in and as the of macrophage colony-stimulating factor R. Salh Gómez-Muñoz A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis through activation of the Lipid Res. Full Text Full Text PDF PubMed Google Scholar). The cells and cultured in the was to in the at in and in with and as a of The was by in the or of inhibitors as Cell was by the of of the as R. Salh Gómez-Muñoz A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis through activation of the Lipid Res. Full Text Full Text PDF PubMed Google Scholar). in ceramide was after BMDMs with for in with and as the for M-CSF as (9Gómez-Muñoz A. Martin A. O'Brien L. Brindley D.N. Cell-permeable ceramides inhibit the stimulation of DNA synthesis and phospholipase D activity by phosphatidate and lysophosphatidate in rat fibroblasts.J. Biol. Chem. 1994; 269: 8937-8943Abstract Full Text PDF PubMed Google Scholar, 10Gómez-Muñoz A. Waggoner D.W. O'Brien L. Brindley D.N. Interaction of ceramides, sphingosine, and sphingosine 1-phosphate in regulating DNA synthesis and phospholipase D activity.J. Biol. Chem. 1995; 270: 26318-26325Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). The was and the cells with The macrophages in this in the or in the of for with and into The cells with a and the and with by of with a and of a 2 and and by The for of with acid and for with to acid The of ceramides was after with by with was by the ceramide from the by DNA was by as previously R. Salh Gómez-Muñoz A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis through activation of the Lipid Res. Full Text Full Text PDF PubMed Google Scholar). cells by in for at with and in of and was with an cell DNA was cellular The of acid sphingomyelinase and sphingomyelinase as by Liu and Hannun B. Hannun Y.A. 1999; Scopus Google Scholar) SM as the SMase to the of protein added to the and the was that of the was The was to the of and to protein to at of for A-SMase activity in cell was in a (9Gómez-Muñoz A. Martin A. O'Brien L. Brindley D.N. Cell-permeable ceramides inhibit the stimulation of DNA synthesis and phospholipase D activity by phosphatidate and lysophosphatidate in rat fibroblasts.J. Biol. Chem. 1994; 269: 8937-8943Abstract Full Text PDF PubMed Google Scholar). in Cer-1-P was after the cells with for in with and as the for The was and cells with M-CSF and The macrophages in this as as and by that as reported (23Hinkovska-Galcheva V.T. Boxer L.A. Mansfield P.J. Harsh D. Blackwood A. Shayman J.A. The formation of ceramide-1-phosphate during neutrophil phagocytosis and its role in liposome fusion.J. Biol. Chem. 1998; 273: 333203-333209Abstract Full Text Full Text PDF Scopus (115) Google Scholar). The for Cer-1-P by with and by and and by and in as R. Salh Gómez-Muñoz A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis through activation of the Lipid Res. Full Text Full Text PDF PubMed Google Scholar). Protein from was and by or to and blocked for with in and and with the in at with with at for and with a for the that was at the of the of are as of in or was with of at It is well known that of growth from of cells cell death apoptosis. is which undergo apoptosis within of M-CSF withdrawal R. Salh Gómez-Muñoz A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis through activation of the Lipid Res. Full Text Full Text PDF PubMed Google Scholar, A. E. R. J.A. of the mitogen-activated protein kinase family in macrophage responses to and Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), in the of We this to the of Cer-1-P macrophage survival. that Cer-1-P increases macrophage after M-CSF withdrawal in a The in cell was at about of of macrophages with Cer-1-P short-chain C2-Cer-1-P and C8-Cer-1-P also increased the of the macrophages after M-CSF to a did natural long-chain Cer-1-P cell survival with C2-Cer-1-P was at and concentrations or resulted in of C2-Cer-1-P of Cer-1-P. However, the of C2-Cer-1-P to at concentrations not direct from Cer-1-P, in ceramide levels a from recent A. Kong J. Salh B. Steinbrecher U. Sphingosine-1-phosphate inhibits sphingomyelinase and blocks apoptosis in macrophages.FEBS Lett. 2003; 539: 56-60Crossref PubMed Scopus (74) Google Scholar), Sph-1-P was also to induce macrophage its was To the effect of Cer-1-P was due to inhibition of apoptosis or to which also these cells for DNA and caspase withdrawal of M-CSF for of cells DNA by of and this was to 2 by Cer-1-P concentrations of acid or sphingosine In addition, Cer-1-P prevented the activation of caspase 9 and the of the by caspase in cell by Cer-1-P. BMDMs as in and for in with M-CSF in the of concentrations of Cer-1-P. Cell was by the as in and are to control cells at of in of different sphingosine-1-phosphate and acid macrophage BMDMs as in and for in M-CSF in the or in the of acetyl octanoyl long-chain Cer-1-P Sph-1-P and acid as Cell was by the as in and are to control cells at of at in inhibits DNA after growth factor withdrawal in BMDMs at in and in with and as the for M-CSF for The was by and cells for in the or in the of Cer-1-P. DNA was by cells as in and in of prevents activation of the caspase-9/caspase-3 BMDMs as in caspase and by as in and for the caspase and for and for caspase 9 and in of In with recent A. Kong J. Salh B. Steinbrecher U. Sphingosine-1-phosphate inhibits sphingomyelinase and blocks apoptosis in macrophages.FEBS Lett. 2003; 539: 56-60Crossref PubMed Scopus (74) Google Scholar, R.S. Gómez-Muñoz A. Salh B. Marotta A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis by ceramide generation thereby activation and Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), M-CSF deprivation caused a in ceramide levels in macrophages of and this was to by Cer-1-P or to C2-Cer-1-P of This that Cer-1-P might cell death by ceramide We previously found that both and SMase stimulated in BMDMs by M-CSF of the SMase activity was to the of the A. Kong J. Salh B. Steinbrecher U. Sphingosine-1-phosphate inhibits sphingomyelinase and blocks apoptosis in macrophages.FEBS Lett. 2003; 539: 56-60Crossref PubMed Scopus (74) Google Scholar, R.S. Gómez-Muñoz A. Salh B. Marotta A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis by ceramide generation thereby activation and Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the that Cer-1-P inhibits the activation of A-SMase in intact cells, thereby the generation of We previously reported that Sph-1-P also inhibits A-SMase activity in intact cells A. Kong J. Salh B. Steinbrecher U. Sphingosine-1-phosphate inhibits sphingomyelinase and blocks apoptosis in macrophages.FEBS Lett. 2003; 539: 56-60Crossref PubMed Scopus (74) Google Scholar). However, these ceramide act A-SMase by different Cer-1-P inhibited SMase activation in cell homogenates, Sph-1-P did not This that the inhibition of A-SMase by Sph-1-P be inhibition by Cer-1-P may involve a direct physical interaction with the enzyme. The effect of Cer-1-P was related little or effect A-SMase activity inhibits A-SMase activation in cell BMDMs M-CSF for to cells and with sphingomyelin with the concentrations of long-chain Cer-1-P C8-Cer-1-P C2-Cer-1-P or Sph-1-P of cells as in the and with concentrations of Cer-1-P acid acid or of A critical was that M-CSF deprivation was with a decrease in the levels of Cer-1-P This that of of Cer-1-P in BMDMs may be of and that the decrease in Cer-1-P at in for the activation of A-SMase that in these cells after M-CSF We previously reported that Cer-1-P and ceramides are In it was that short-chain or natural long-chain DNA synthesis was inhibited by cell-permeable ceramides (21Gómez-Muñoz A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar, 22Gómez-Muñoz A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar). not its blocked macrophage survival thereby the for cells to an balance in the levels of intracellular ceramide and Cer-1-P. The of Cer-1-P to cell proliferation was first reported by Gómez-Muñoz et al. (21Gómez-Muñoz A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar) short-chain and C8-Cer-1-P (21Gómez-Muñoz A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar), or natural long-chain Cer-1-P A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar). by an in the levels of cell A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar). More recently, Frago et al. L.M. Y. Gómez-Muñoz A. Varela-Nieto I. growth factor and ceramides cell death in the early Cell 1998; PubMed Google Scholar) that C8-Cer-1-P caused a in the of cultured vesicle In that C8-Cer-1-P also cell death in the caused by suggesting that Cer-1-P might have or L.M. Y. Gómez-Muñoz A. Varela-Nieto I. growth factor and ceramides cell death in the early Cell 1998; PubMed Google Scholar). The of action of Cer-1-P to from that of as Sph-1-P and in that Cer-1-P not the activity of or adenylyl cyclase, which are in the regulation of cell proliferation A. Waggoner D.W. O'Brien L. Brindley D.N. Interaction of ceramides, sphingosine, and sphingosine 1-phosphate in regulating DNA synthesis and phospholipase D activity.J. Biol. Chem. 1995; 270: 26318-26325Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, S. Olivera A. Carlson R.O. The role of sphingosine in cell growth regulation and transmembrane signaling.Adv. Lipid Res. 1993; 25: 105-127PubMed Google Scholar, 13Spiegel S. Milstien S. Sphingosine 1-phosphate, a key cell signaling molecule.J. Biol. Chem. 2002; 277: 25851-25854Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar, 22Gómez-Muñoz A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar, A. of cell by 1998; PubMed Scopus Google Scholar, S. D. Kolesnick R. through lipid second Cell Biol. 1996; PubMed Scopus Google Scholar). In addition, we now show that Cer-1-P blocks DNA and caspase activation in suggesting that its effect in these cells is due to inhibition of apoptosis. In a we that apoptosis of BMDMs induced by M-CSF withdrawal stimulation of A-SMase activity and the of ceramides A. Kong J. Salh B. Steinbrecher U. Sphingosine-1-phosphate inhibits sphingomyelinase and blocks apoptosis in macrophages.FEBS Lett. 2003; 539: 56-60Crossref PubMed Scopus (74) Google Scholar). activation to a role in apoptosis in these cells, a sphingomyelinase prevents ceramide and blocks apoptosis (26Hundal R.S. Gómez-Muñoz A. Salh B. Marotta A. Duronio V. Steinbrecher U.P. Oxidized low density inhibits macrophage apoptosis by ceramide generation thereby activation and Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). More direct evidence that A-SMase activation and ceramide generation are for apoptosis after M-CSF withdrawal in macrophages was in BMDMs from A-SMase by with BMDMs that these cells are to apoptosis after M-CSF withdrawal Gómez-Muñoz, In the we demonstrate that Cer-1-P inhibits A-SMase activation in thereby the of This effect of Cer-1-P a direct physical interaction with the Cer-1-P can also inhibit A-SMase activity in cell This also that the effect of Cer-1-P intact cells is not mediated through It is that Cer-1-P through to is little or conversion of Cer-1-P to Sph-1-P M. Kono K. Liu H. Shimizugawa T. Minekura H. Spiegel S. Kohama T. Ceramide kinase, a novel lipid kinase.J. Biol. Chem. 2002; 277: 23294-23300Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, A. Duffy P.A. Martin A. O'Brien L. Byun H.S. Bittman R. Brindley D.N. Short-chain ceramide 1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.Mol. Pharmacol. 1995; 47: 883-889Google Scholar, 22Gómez-Muñoz A. Frago L. Alvarez L. Varela-Nieto I. Stimulation of DNA synthesis by natural ceramide 1-phosphate.Biochem. J. 1997; 325: 435-440Crossref PubMed Scopus (120) Google Scholar, R. S.M. phosphatase activity in 1993; PubMed Scopus Google Scholar). we that Sph-1-P not inhibit A-SMase activity in cell homogenates, suggesting that it not affect A-SMase in the that Cer-1-P The of the effect of Cer-1-P is by that the intracellular levels of Cer-1-P are in the macrophages after M-CSF This A-SMase from thereby ceramide generation and cell The Kolesnick for the of acid sphingomyelinase This was by from and from is the of a from the and of acid sphingomyelinase bone marrow-derived macrophages acetyl octanoyl ceramide-1-phosphate kinase mitogen-activated protein kinase macrophage colony-stimulating factor sphingosine-1-phosphate

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