Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sphingosine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources
PubMed2004

The intracellular action of sphingosine 1-phosphate in GPVI-mediated Ca2+ mobilization in platelets.

We analyzed the intracellular action of sphingosine 1-phosphate (Sph-1-P), formed from sphingosine (Sph) by sphingosine kinase (SPHK), in platelets. When sphingosine kinase activity was inhibited by N,N-dimethylsphingosine (DMS), Ca2+ mobilization induced by convulxin, an agonist of the collagen receptor glycoprotein VI (GPVI), was moderately but specifically abolished; that induced via G protein-coupled receptors was not affected. Under the same conditions, however, tyrosine phosphorylation of Syk and phospholipase Cgamma2, which is essential for the GPVI-mediated signaling, was not inhibited. Sphingosine kinase activity of the platelet membrane fraction increased specifically upon stimulation with convulxin or collagen. Our results suggest that intracellular sphingosine 1-phosphate is related to Ca2+ mobilization in GPVI-mediated signaling pathways.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Assessment of the extracellular and intracellular actions of sphingosine 1-phosphate by using the p42/p44 mitogen-activated protein kinase cascade as a model.

We have investigated the extracellular and intracellular actions of sphingosine 1-phosphate (S1P) by using cultured airway smooth muscle cells. We have demonstrated that exogenous S1P elicited an activation of mitogen-activated protein kinase (p42/p44 MAPK) that was abolished by pertussis toxin (0.1 microg/mL, 24 h), which was used to inactivate Gi. The effect of exogenous S1P might therefore be attributed to an action at a putative Gi-coupled receptor. The regulation of the p42/p44 MAPK cascade by S1P was also shown to include a protein kinase C (PKC)-dependent intermediate step. Platelet-derived growth factor (PDGF) stimulates intracellular S1P formation and was therefore used to evaluate the intracellular action of S1P. This has previously been investigated by others using the sphingosine kinase inhibitors D,L-threo-dihydrosphingosine and N,N-dimethylsphingosine. We have demonstrated here that both inhibitors block the PDGF-dependent activation of p42/p44 MAPK. However, both are also PKC inhibitors, which might account for their effect because PDGF utilises PKC as an intermediate in the regulation of the p42/p44 MAPK cascade. Significantly, sphingosine, which is the substrate of sphingosine kinase and a PKC inhibitor, blocked the activation of p42/p44 MAPK by PDGF with an almost identical concentration dependence compared with D,L-threo-dihydrosphingosine and N,N-dimethylsphingosine. Therefore, the use of so-called sphingosine kinase inhibitors might lead to misleading interpretations because of their additional effect on PKC. Other approaches, such as oligodeoxynucleotide anti-sense against sphingosine kinase, are required to address the intracellular role of S1P.

Animals↗
PubMed1998

Characterization of sphingosine kinase (SK) activity in Saccharomyces cerevisiae and isolation of SK-deficient mutants.

Sphingosine kinase (SK) catalyses the phosphorylation of sphingosine to generate sphingosine 1-phosphate, which is a second messenger involved in the proliferative responses of mammalian cells. Although the yeast Saccharomyces cerevisiae has similar phosphorylated sphingoid bases which appear to be involved in growth regulation and the response to stress, SK activity had not been previously demonstrated in yeast. In this study, an in vitro system was set up to characterize yeast SK activity. Activity was detected in the cytosol at neutral pH and 37 degreesC. Yeast SK phosphorylated the sphingoid bases sphingosine, dihydrosphingosine and phytosphingosine. (d,l)-threo-dihydrosphingosine, an inhibitor of mammalian SK, did not inhibit the yeast enzyme. Unique properties of yeast SK were an optimal temperature of 43 degreesC, and in vivo activation during nutrient deprivation. Spontaneous mutants with diminished SK activity were isolated utilizing a screen for resistance to sphingosine in a sphingosine-phosphate-lyase deletion background. Abnormal growth and heat sensitivity were observed in these mutants. These findings suggest that SK may function as a stress-response protein in yeast.

Cell Division↗
PubMed2001

1Alpha,25-dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate.

Owing to its ability to induce growth arrest and differentiation of keratinocytes, 1alpha,25-dihydroxyvitamin D3 and its analogs are useful for the treatment of hyperproliferative skin diseases, such as psoriasis vulgaris. It has been implicated that the 1alpha,25-dihydroxyvitamin D3-induced differentiation of keratinocytes is mediated, at least in part, by the formation of ceramides; however, ceramides have also been identified to induce apoptosis in many cells, including keratinocytes. Therefore, it was of interest to investigate the influence of 1alpha,25-dihydroxyvitamin D3 on apoptosis in keratinocytes. Most interestingly, physiological concentrations of 1alpha,25-dihydroxyvitamin D3 did not induce apoptosis in keratinocytes, despite the formation of ceramides. Moreover, 1alpha,25-dihydroxyvitamin D3 appeared cytoprotective and made keratinocytes resistant to apoptosis induced by ceramides, ultraviolet irradiation, or tumor necrosis factor-alpha. The cytoprotective effect was accompanied by the formation of the sphingolipid breakdown product sphingosine-1-phosphate, which prevented apoptosis in analogy to 1alpha,25-dihydroxyvitamin D3. The effect of 1alpha,25-dihydroxyvitamin D3 was specific as the almost inactive precursor cholecalciferol neither induced sphingosine-1-phosphate formation nor prevented cells from apoptosis. Besides this, the cytoprotective aptitude of 1alpha,25-dihydroxyvitamin D3 was completely abolished by the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocked sphingosine-1-phosphate formation. Moreover, sphingosine-1-phosphate was able to restore the cytoprotective effect of 1alpha,25-dihydroxyvitamin D3 in the presence of N,N-dimethylsphingosine. Taken together, here we report for the first time that 1alpha,25-dihydroxyvitamin D3 protects keratinocytes from apoptosis and additionally this cytoprotection is mediated via the formation of sphingosine-1-phosphate.

Apoptosis↗
PubMed1997

Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors. Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling.

Platelet-derived growth factor (PDGF) and serum, but not epidermal growth factor (EGF), stimulated sphingosine kinase activity in Swiss 3T3 fibroblasts and increased intracellular concentrations of sphingosine 1-phosphate (SPP), a sphingolipid second messenger (Olivera, A., and Spiegel, S. (1993) Nature 365, 557-560). We report herein that DL-threo-dihydrosphingosine (DHS), a competitive inhibitor of sphingosine kinase that prevents PDGF-induced SPP formation, specifically inhibited the activation of two cyclin-dependent kinases (p34(cdc2) kinase and Cdk2 kinase) induced by PDGF, but not by EGF. SPP reversed the inhibitory effects of DHS on PDGF-stimulated cyclin-dependent kinases and DNA synthesis, demonstrating that the DHS effects were mediated via inhibition of sphingosine kinase. DHS also markedly reduced PDGF-stimulated but not EGF-stimulated mitogen-activated protein kinase activity and DNA binding activity of activator protein-1. Examination of the early signaling events of PDGF action revealed that DHS did not affect PDGF-induced autophosphorylation of the growth factor receptor or phosphorylation of the SH2/SH3 adaptor protein Shc and its association with Grb2. This sphingosine kinase inhibitor did not abrogate activation of phosphatidylinositol 3-kinase by PDGF. In agreement, treatment with SPP had no effect on these responses but did, however, potently stimulate phosphorylation of Crk, another SH2/SH3 adaptor protein. Moreover, DHS inhibited PDGF-stimulated, but not EGF-stimulated, Crk phosphorylation. Thus, regulation of sphingosine kinase activity defines divergence in signal transduction pathways of PDGF and EGF receptors leading to mitogen-activated protein kinase activation.

3T3 Cells↗
PubMed2004

Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720.

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs of Sphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

Animals↗
PubMed1998

Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors.

Formation of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC) with subsequent release of Ca2+ from intracellular stores, is one of the major Ca2+ signalling pathways triggered by G-protein-coupled receptors (GPCRs). However, in a large number of cellular systems, Ca2+ mobilization by GPCRs apparently occurs independently of the PLC-IP3 pathway, mediated by an as yet unknown mechanism. The present study investigated whether sphingosine kinase activation, leading to production of sphingosine-1-phosphate (SPP), is involved in GPCR-mediated Ca2+ signalling as proposed for platelet-derived growth factor and FcepsilonRI antigen receptors. Inhibition of sphingosine kinase by DL-threo-dihydrosphingosine and N,N-dimethylsphingosine markedly inhibited [Ca2+]i increases elicited by m2 and m3 muscarinic acetylcholine receptors (mAChRs) expressed in HEK-293 cells without affecting mAChR-induced PLC stimulation. Activation of mAChRs rapidly and transiently stimulated production of SPP in HEK-293 cells. Finally, intracellular injection of SPP induced a rapid and transient Ca2+ mobilization in HEK-293 cells which was not antagonized by heparin. We conclude that mAChRs utilize the sphingosine kinase-SPP pathway in addition to PLC-IP3 to mediate Ca2+ mobilization. As Ca2+ signalling by various, but not all, GPCRs in different cell types was likewise attenuated by the sphingosine kinase inhibitors, we suggest a general role for sphingosine kinase, besides PLC, in mediation of GPCR-induced Ca2+ signalling.

Animals↗
PubMed2003

Differential branching of the sphingolipid metabolic pathways with the stage of development. Involvement of sphingosine kinase.

We have studied sphingomyelin metabolism in the papillae of neonatal (10-day-old) and adult (70-day-old) kidneys of male Wistar rats because sphingolipid second messengers generated by sphingomyelin metabolism are involved in cellular processes such as proliferation, differentiation and apoptosis. We showed that sphingomyelin and ceramide concentrations in homogenized rat papilla tissue increase with the time whereas sphingosine-1-phosphate content decreases. This is consistent with the finding of a higher biosynthesis of the latter sphingolipid in neonatal than in adult rat papillae. De novo synthetized ceramide was, however, higher in adult than in neonatal papilla homogenates probably accounting for the high ceramide content of the adult rat papilla. These results suggest an active de novo pathway not ending in sphingomyelin but instead arresting at ceramide in adult rat papilla tissue, partially metabolized into sphingosine-1-phosphate in neonatal rat papillae. The activity and the expression of sphingosine kinase, one of the enzymes involved in ceramide metabolism, was found to be higher in neonatal than adult rat kidney tissue. The intracellular distribution of sphingosine kinase was also different; in neonatal rat tissue the enzyme was predominantly associated with plasma membranes but it was cytosolic in adult rat papilla tissue. These findings seem to indicate that, in rat renal papillae, the developmental regulation of sphingosine kinase expression and activity addresses the sphingolipid metabolism to the formation of the proliferative metabolite sphingosine-1-phosphate in the neonatal period, and ceramide, which is associated with cell arrest and differentiation in the adult tissue. These data are consistent with the proliferative state necessary for tubular elongation during the neonatal period and the maintenance of the differentiated state in the adult tissue.

Aging↗
PubMed2006

Sphingosine kinase: biochemical and cellular regulation and role in disease.

Sphingolipids have emerged as molecules whose metabolism is regulated leading to generation of bioactive products including ceramide, sphingosine, and sphingosine-1-phosphate. The balance between cellular levels of these bioactive products is increasingly recognized to be critical to cell regulation; whereby, ceramide and sphingosine cause apoptosis and growth arrest phenotypes, and sphingosine-1-phosphate mediates proliferative and angiogenic responses. Sphingosine kinase is a key enzyme in modulating the levels of these lipids and is emerging as an important and regulated enzyme. This review is geared at mechanisms of regulation of sphingosine kinase and the coming to light of its role in disease.

Animals↗
PubMed1997

Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation.

Sphingolipid metabolites, such as ceramide and sphingosine-1-phosphate (SPP), are emerging as a new class of second messengers involved in cellular proliferation, differentiation, and apoptosis. Nerve growth factor (NGF), a neurotrophic factor for pheochromocytoma PC12 cells, induced a biphasic increase in the activity of sphingosine kinase, the enzyme that catalyzes the formation of SPP. This activation was blocked by K252a, an inhibitor of tyrosine kinase A (trkA). A rapid 1.7-fold increase was followed by a marked prolonged increase reaching a maximum of fourfold to fivefold stimulation with a concomitant increase in SPP levels and a corresponding decrease in endogenous sphingosine levels. Levels of ceramide, the precursor of sphingosine, were only slightly decreased by NGF in serum-containing medium. However, NGF decreased the elevation of ceramide induced by serum withdrawal. Treatment of PC12 cells with SPP did not induce neurite outgrowth or neurofilament expression, yet it enhanced neurofilament expression elicited by suboptimal doses of NGF. Moreover, SPP also protected PC12 cells from apoptosis induced by serum withdrawal. To further substantiate a role for SPP in the cytoprotective actions of NGF, we found that N, N-dimethylsphingosine, a competitive inhibitor of sphingosine kinase, also induced apoptosis and interfered with the survival effect of NGF. These effects were counteracted by exogenous SPP. Moreover, other structurally related compounds, such as dihydrosphingosine 1-phosphate and lysophosphatidic acid, had no significant protective effects. Our results suggest that activation of sphingosine kinase and subsequent formation of SPP may play an important role in the differentiation and survival effects induced by NGF.

Animals↗
PubMed1995

Effects of sphingosine derivatives on MC3T3-E1 pre-osteoblasts: psychosine elicits release of calcium from intracellualr stores.

Sphingosine, sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPC) each elicited transient elevations in intracellular free Ca2+ ([Ca2+]i) as a result of Ca2+ release from an intracellular store in MC3T3-E1 pre-osteoblasts. No elevation in [Ca2+]i was detected in response to the application of N-acetyl sphingosine. Psychosine (1-galactosyl sphingosine) also caused Ca2+ release from intracellular stores, which suggests that phosphorylation of the 1-carbon of sphingosine is not required for its action as a Ca2+ release agonist in MC3T3-E1 cells. Sequential additions of combinations of sphingosine, SPP, SPC and psychosine revealed Ca2+ transients only after the application of the first sphingolipid, despite the fact that the intracellular Ca2+ stores refilled. This indicates that each agent desensitized the MC3T3-E1 cells to the action of the others and suggests that all of the sphingolipids tested employ the same receptor or a common intracellular messenger.

3T3 Cells↗
PubMed1995

The mechanism of sphingosine enhancement of phorbol ester-mediated phospholipase D activation in lymphocytes.

Tumor-promoting phorbol esters stimulate the production of phosphatidylethanol (PEt) in bovine lymph node lymphocytes through the activation of Phospholipase D (PLD). Sphingosine enhanced the 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated formation of PEt in lymphocytes, while it had no effect by itself. Interestingly, the incorporation of labeled arachidonic acid into phospholipids was increased by sphingosine. Examination of the effect of sphingosine along with TPA on the incorporation of [1-14C]labeled-arachidonic acid into individual phospholipids revealed that they enhanced significantly the specific activity of only PC and lyso-PC fractions. These observations indicate that sphingosine does not activate PLD directly as TPA does. It appears that sphingosine increases the specific radioactivity of the substrate pool for PLD which results in an apparent increase in PEt when both sphingosine and TPA are present.

Animals↗
PubMed1998

Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast.

Sphingosine-1-phosphate (S-1-P) has been shown to participate in the proliferative signal transduction pathways of mammalian cells. Sphingosine-1-phosphate lyase (SPL) catalyzes the breakdown of S-1-P. Using the C. elegans SPL nucleotide sequence, we identified a mouse EST as a putative candidate for the homologous gene encoding this enzyme. Sequencing of the mouse EST revealed an open reading frame of 1707 nucleotides. This putative mouse SPL gene is 62% similar and 39% identical to the C. elegans SPL gene and 59% homologous and 39.6% identical to the yeast SPL gene. Expression of the mouse SPL gene in a yeast strain-delta bst1, which carries a deletion of the SPL gene and is hypersensitive to sphingosine, restored a sphingosine-resistant phenotype, suggesting this mouse gene can functionally complement the yeast defect when expressed. In vitro enzyme assay using extracts from these sphingosine-resistant transformants confirmed the SPL activities encoded by this mouse cDNA clone. Northern analysis indicated the mouse SPL gene is expressed at various levels in different tissues. Chromosomal localization mapped this SPL gene to Chromosome 10 at 32 cM. Here, we report the identification of the first mammalian sphingosine phosphate lyase gene.

Aldehyde-Lyases↗
PubMed1993

Sphingosine blocks both membrane fusion and calmodulin-dependent phosphorylation of the 100-kDa protein of chick embryonic myoblasts.

Sphingosine, a potent inhibitor of protein kinase C, was found to block membrane fusion of chick embryonic myoblasts in culture. This effect was dose-dependent and could be reversed upon removal of the drug. Treatment with 12-O-tetradecanoylphorbol 13-acetate, which is a powerful activator of protein kinase C and capable of preventing myoblast fusion, further potentiated the inhibitory effect of sphingosine. Thus, the sphingosine-mediated inhibition of myoblast fusion appears to be independent of protein kinase C. Sphingosine also decreased the phosphorylation state of the 100-kDa protein when given to the cell extracts, and this inhibition was competitive with calmodulin. Thus, sphingosine seems to act as a calmodulin antagonist. These results suggest that the sphingosine-mediated inhibition of myoblast fusion may be associated with the inhibitory effect of the drug against the calmodulin-dependent phosphorylation of the 100-kDa protein.

Animals↗
PubMed1993

Alteration of tissue and serum sphinganine to sphingosine ratio: an early biomarker of exposure to fumonisin-containing feeds in pigs.

Fumonisins are a group of naturally occurring compounds produced by the fungus Fusarium moniliforme. They are believed to be the etiologic agent of several animal diseases associated with consumption of corn-based feeds including porcine pulmonary edema. Recently it was shown in vitro that fumonisins are specific inhibitors of sphingosine and sphinganine N-acyltransferases. Inhibition of these enzymes in cultured cells results in the accumulation of free long chain sphingoid bases, specifically sphingosine and sphinganine, and the depletion of complex sphingolipids. In this study, tissues and serum from male SPF pigs fed a nutritionally balanced diet containing corn or corn screenings naturally contaminated with fumonisins for up to 14 days were analyzed for free sphingoid bases and complex sphingolipids. Total fumonisins (B1 and B2) in the diets were analyzed at 0 (< 1), 5, 23, 39, 101, and 175 ppm. Pulmonary edema only occurred at 175 ppm, while histologic liver damage was present at > or = 23 ppm, and serum liver enzymes were significantly elevated at > or = 101 ppm. The results of this study show that free sphinganine is elevated in liver, lung, and kidney, from pigs consuming feeds containing fumonisins at total fumonisin concentrations of 23 ppm or greater. Sphingosine is also elevated in a dose-dependent manner, but to a lesser extent than sphinganine. The consequence of this differential inhibition is that the ratio of sphinganine to sphingosine increases, suggesting that sphinganine N-acyltransferase is the preferred target for fumonisins. Elevation of free sphinganine and free sphingosine in serum paralleled the increases in tissues. Statistically significant increases in the ratio were observed at feed concentrations as low as 5 ppm total fumonisins and in pigs (at higher concentrations) in which other serum biochemistry parameters and tissue morphology were not altered. Elevated ratios were also observed in serum from pigs fed pure fumonisin B1. The sensitivity of the ratio indicates that it could serve as an effective biomarker for consumption of fumonisin-containing feeds. In addition, the data supports the hypothesis that inhibition of sphingosine and sphinganine N-acyltransferase plays an important role in the pathogenesis of animal diseases associated with consumption of feed containing fumonisins.

Animal Feed↗
PubMed1994

Sphingosine regulates Ca(2+)-ATPase and reloading of intracellular Ca2+ stores in the pancreatic acinar cell.

The purpose of present study was to examine the effects of sphingosine on cellular Ca2+ transports using dispersed rat pancreatic acini. The results demonstrated that sphingosine had a specific effect to inhibit Ca2+ uptake into the cell's agonist-sensitive pool as well as inhibiting microsomal Ca(2+)-ATPase. The ability of sphingosine to inhibit Ca2+ uptake resulted in both augmentation of Ca2+ release from the pool by inositol 1,4,5-trisphosphate (IP3) and conversion of the Ca2+ release by inositol 1,4,5-trisphosphate from a transient response to a sustained response. Furthermore, by preventing Ca2+ pool refilling sphingosine mimicked the effect of the agonist, carbachol, to maintain an increased [Ca2+]i during sustained stimulation. These results suggest that regulation of Ca(2+)-ATPase by sphingosine or a sphingosine-like agent mediates some of the effects of agonist on cell Ca2+ transports.

Animals↗
PubMed1994

Sphingosine-like stimulatory effects of propranolol on phospholipase D activity in NIH 3T3 fibroblasts.

Propranolol and sphingosine exhibit several common biochemical effects, including inhibition of phosphatidic acid phosphohydrolase and protein kinase C (PKC) activities. In NIH 3T3 fibroblasts, sphingosine has also been shown to stimulate phospholipase D (PLD)-mediated hydrolysis of both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) (Kiss Z and Anderson WB, J Biol Chem 265: 7345-7350, 1990). The present study demonstrates that in [14C]palmitic acid-labeled NIH 3T3 fibroblasts, propranolol (50-100 microM) and sphingosine had similar stimulatory effects on PLD-mediated synthesis of phosphatidylethanol in the presence of ethanol. In [14C]choline- and [14C]-ethanolamine-labeled fibroblasts, both compounds also stimulated the hydrolysis of both [14C]PtdCho and [14C]PtdEtn. However, while sphingosine preferentially stimulated PtdEtn hydrolysis, propranolol had greater effects on PtdCho hydrolysis. At each time point examined (15-45 min), lower concentrations (25-50 microM) of propranolol and 100 nM phorbol 12-myristate 13-acetate (PMA) synergistically enhanced PtdEtn hydrolysis; a higher concentration (100 microM) of propranolol inhibited this PMA effect only when the incubation time was 45 min. On the other hand, propranolol (10-100 microM) had either no effect or it inhibited PMA-induced PtdCho hydrolysis after treatments for 15 or 45 min, respectively. These potentiating and inhibitory actions of propranolol on the hydrolysis of PtdCho and PtdEtn were similarly elicited by sphingosine. The present study identified the PLD system as another common target for the pharmacological actions of sphingosine and propranolol.

3T3 Cells↗
PubMed1994

A possible role of sphingosine in induction of apoptosis by tumor necrosis factor-alpha in human neutrophils.

Treatment of human neutrophils with tumor necrosis factor-alpha (TNF-alpha) resulted in an increase in concentration of ceramide and its catabolite, sphingosine. Sphingosine, a potent endogenous protein kinase C (PKC) inhibitor, as well as TNF-alpha, induced internucleosomal DNA fragmentation and morphological changes characteristic of apoptotic cells. Ceramide and sphingosine-1-phosphate, the initial product of sphingosine catabolism, did not cause apoptosis under our experimental conditions. In addition, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) and N,N-dimethylsphingosine (DMS), known as PKC inhibitors, also induced apoptosis, suggesting that induction of apoptosis by sphingosine may be related to inhibition of PKC activity. These results indicate that sphingosine deacylated from ceramide may be an endogenous modulator mediating apoptotic signals by TNF-alpha in neutrophils.

Apoptosis↗