Sphingolipid Metabolism in Systemic Inflammation

  • H. P. Deigner
  • E. Gulbins
  • R. A. Claus
Conference paper
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 2007)


The inflammatory response — induced and regulated by a variety of mediators such as cytokines, prostaglandins, and reactive oxygen species (ROS) — is the localized host’s response of the tissue to injury, irritation, or infection. In a very similar and stereotyped sequence, the mediators are thought to induce an acute phase response orchestrated by an array of substances produced locally or near the source or origin of the inflammatory response. Despite its basically protective function, the response can become inappropriate in intensity or duration damaging host tissues or interfering with normal metabolism. Thus, inflammation is the cause and/or consequence of a diversity of diseases and plays a major role in the development of remote organ failure. Better knowledge of the underlying mechanisms of these processes is, therefore, a fundamental pre-requisite fostering the molecular understanding of novel therapeutic targets or diagnostic variables.


Sphingosine Kinase Hemophagocytic Lymphohistiocytosis Sphingolipid Metabolism Acid Sphingomyelinase Neutral Sphingomyelinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Chalfant CE, Spiegel S (2005) Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 118:4605–4612CrossRefPubMedGoogle Scholar
  2. 2.
    Baumruker T, Prieschl EE (2002) Sphingolipids and the regulation of the immune response. Semin Immunol 14:57–63CrossRefPubMedGoogle Scholar
  3. 3.
    Pettus BJ, Chalfant CE, Hannun YA (2004) Sphingolipids in inflammation: roles and implications. Curr Mol Med 4:405–418CrossRefPubMedGoogle Scholar
  4. 4.
    Hinkovska-Galcheva V, Boxer LA, Kindzelskii A, et al (2005) Ceramide 1-phosphate, a mediator of phagocytosis. J Biol Chem 280:26612–26621CrossRefPubMedGoogle Scholar
  5. 5.
    Gomez-Munoz A, Kong JY, Salh B, Steinbrecher UP (2004) Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages. J Lipid Res 45:99–105CrossRefPubMedGoogle Scholar
  6. 6.
    van Meer G, Lisman Q (2002) Sphingolipid transport: rafts and translocators. J Biol Chem 277:25855–25858CrossRefPubMedGoogle Scholar
  7. 7.
    Birbes H, Luberto C, Hsu YT, El Bawab S, Hannun YA, Obeid LM (2005) A mitochondrial pool of sphingomyelin is involved in TNFalpha-induced Bax translocation to mitochondria. Biochem J 386:445–451CrossRefPubMedGoogle Scholar
  8. 8.
    Paris F, Grassme H, Cremesti A, et al (2001) Natural ceramide reverses Fas resistance of acid sphingomyelinase(-/-) hepatocytes. J Biol Chem 276:8297–8305CrossRefPubMedGoogle Scholar
  9. 9.
    Heinrich M, Wickel M, Winoto-Morbach S, et al (2000) Ceramide as an activator lipid of cathepsin D. Adv Exp Med Biol 477:305–315CrossRefPubMedGoogle Scholar
  10. 10.
    Alessenko A, Chatterjee S (1995) Neutral sphingomyelinase: localization in rat liver nuclei and involvement in regeneration/proliferation. Mol Cell Biochem 143:169–174CrossRefPubMedGoogle Scholar
  11. 11.
    Gulbins E, Li PL (2006) Physiological and pathophysiological aspects of ceramide. Am J Physiol Regul Integr Comp Physiol 290:R11–26PubMedGoogle Scholar
  12. 12.
    Goni FM, Alonso A (2002) Sphingomyelinases: enzymology and membrane activity. FEBS Lett 531:38–46CrossRefPubMedGoogle Scholar
  13. 13.
    Marchesini N, Hannun YA (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 82:27–44CrossRefPubMedGoogle Scholar
  14. 14.
    Schneider PB, Kennedy EP (1967) Sphingomyelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. J Lipid Res 8:202–209PubMedGoogle Scholar
  15. 15.
    Tomiuk S, Zumbansen M, Stoffel W (2000) Characterization and subcellular localization of murine and human magnesium-dependent neutral sphingomyelinase. J Biol Chem 275:5710–5717CrossRefPubMedGoogle Scholar
  16. 16.
    Czarny M, Liu J, Oh P, Schnitzer JE (2003) Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate ceramide. J Biol Chem 278:4424–4430CrossRefPubMedGoogle Scholar
  17. 17.
    Hofmann K, Tomiuk S, Wolff G, Stoffel W (2000) Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proc Natl Acad Sci USA 97:5895–5900CrossRefPubMedGoogle Scholar
  18. 18.
    Adam-Klages S, Schwandner R, Adam D, Kreder D, Bernardo K, Kronke M (1998) Distinct adapter proteins mediate acid versus neutral sphingomyelinase activation through the p55 receptor for tumor necrosis factor. J Leukoc Biol 63:678–682PubMedGoogle Scholar
  19. 19.
    Veldman RJ, Maestre N, Aduib OM, Medin JA, Salvayre R, Levade T (2001) A neutral sphingomyelinase resides in sphingolipid-enriched microdomains and is inhibited by the caveolin-scaffolding domain: potential implications in tumour necrosis factor signalling. Biochem J 355:859–868PubMedGoogle Scholar
  20. 20.
    Levy M, Castillo SS, Goldkorn T (2006) nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis. Biochem Biophys Res Commun 344:900–905CrossRefPubMedGoogle Scholar
  21. 21.
    Tabas I (1999) Secretory sphingomyelinase. Chem Phys Lipids 102:123–130CrossRefPubMedGoogle Scholar
  22. 22.
    Schissel SL, Keesler GA, Schuchman EH, Williams KJ, Tabas I (1998) The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J Biol Chem 273:18250–18259CrossRefPubMedGoogle Scholar
  23. 23.
    Dhami R, Schuchman EH (2004) Mannose 6-phosphate receptor-mediated uptake is defective in acid sphingomyelinase-deficient macrophages: implications for Niemann-Pick disease enzyme replacement therapy. J Biol Chem 279:1526–1532CrossRefPubMedGoogle Scholar
  24. 24.
    Ni X, Morales CR (2006) The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor. Traffic 7:889–902CrossRefPubMedGoogle Scholar
  25. 25.
    Marathe S, Schissel SL, Yellin MJ, et al (1998) Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. Implications for early atherogenesis and ceramide-mediated cell signaling. J Biol Chem 273:4081–4088CrossRefPubMedGoogle Scholar
  26. 26.
    Callahan JW, Jones CS, Davidson DJ, Shankaran P (1983) The active site of lysosomal sphingomyelinase: evidence for the involvement of hydrophobic and ionic groups. J Neurosci Res 10:151–163CrossRefPubMedGoogle Scholar
  27. 27.
    Schissel SL, Jiang X, Tweedie-Hardman J, et al (1998) Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem 273:2738–2746CrossRefPubMedGoogle Scholar
  28. 28.
    Niwa M, Kozawa O, Matsuno H, Kanamori Y, Hara A, Uematsu T (2000) Tumor necrosis factor-alpha-mediated signal transduction in human neutrophils: involvement of sphingomyelin metabolites in the priming effect of TNF-alpha on the fMLP-stimulated superoxide production. Life Sci 66:245–256CrossRefPubMedGoogle Scholar
  29. 29.
    MacKinnon AC, Buckley A, Chilvers ER, Rossi AG, Haslett C, Sethi T (2002) Sphingosine kinase: a point of convergence in the action of diverse neutrophil priming agents. J Immunol 169:6394–6400PubMedGoogle Scholar
  30. 30.
    Prieschl EE, Csonga R, Novotny V, Kikuchi GE, Baumruker T (1999) The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc epsilon receptor I triggering. J Exp Med 190:1–8CrossRefPubMedGoogle Scholar
  31. 31.
    Alemany R, Meyer zu Heringdorf D, van Koppen CJ, Jakobs KH (1999) Formyl peptide receptor signaling in HL-60 cells through sphingosine kinase. J Biol Chem 274: 3994–3999CrossRefPubMedGoogle Scholar
  32. 32.
    Bollinger CR, Teichgraber V, Gulbins E (2005) Ceramide-enriched membrane domains. Biochim Biophys Acta 1746:284–294CrossRefPubMedGoogle Scholar
  33. 33.
    Grassme H, Cremesti A, Kolesnick R, Gulbins E (2003) Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22:5457–5470CrossRefPubMedGoogle Scholar
  34. 34.
    Gulbins E (2003) Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol Res 47:393–399CrossRefPubMedGoogle Scholar
  35. 35.
    Gulbins E, Grassme H (2002) Ceramide and cell death receptor clustering. Biochim Biophys Acta 1585:139–145PubMedGoogle Scholar
  36. 36.
    Miyaji M, Jin ZX, Yamaoka S, et al (2005) Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis. J Exp Med 202: 249–59.CrossRefPubMedGoogle Scholar
  37. 37.
    Gulbins E, Dreschers S, Wilker B, Grassme H (2004) Ceramide, membrane rafts and infections. J Mol Med 82:357–363CrossRefPubMedGoogle Scholar
  38. 38.
    Gulbins E, Kolesnick R (2003) Raft ceramide in molecular medicine. Oncogene 22:7070–7077CrossRefPubMedGoogle Scholar
  39. 38.
    Simons K, Ehehalt R (2002) Cholesterol, lipid rafts, and disease. J Clin Invest 110:597–603PubMedGoogle Scholar
  40. 40.
    Grassme H, Jendrossek V, Riehle A, et al (2003) Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med 9:322–330CrossRefPubMedGoogle Scholar
  41. 41.
    Ghosh S, Bhattacharyya S, Das S, et al (2001) Generation of ceramide in murine macrophages infected with Leishmania donovani alters macrophage signaling events and aids intracellular parasitic survival. Mol Cell Biochem 223:47–60CrossRefPubMedGoogle Scholar
  42. 42.
    Grassme H, Riehle A, Wilker B, Gulbins E (2005) Rhinoviruses infect human epithelial cells via ceramide-enriched membrane platforms. J Biol Chem 280:26256–26262CrossRefPubMedGoogle Scholar
  43. 43.
    Josephs M, Katan M, Rodrigues-Lima F (2002) Irreversible inactivation of magnesium-dependent neutral sphingomyelinase 1 (NSM1) by peroxynitrite, a nitric oxide-derived oxidant. FEBS Lett 531:329–334CrossRefPubMedGoogle Scholar
  44. 44.
    Won JS, Singh I (2006) Sphingolipid signaling and redox regulation. Free Radic Biol Med 40:1875–1888CrossRefPubMedGoogle Scholar
  45. 45.
    Claus RA, Bunck AC, Bockmeyer CL, et al (2005) Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis. Faseb J 19:1719–1721PubMedGoogle Scholar
  46. 46.
    Qiu H, Edmunds T, Baker-Malcolm J, et al (2003) Activation of human acid sphingomyelinase through modification or deletion of C-terminal cysteine. J Biol Chem 278: 32744–32752CrossRefPubMedGoogle Scholar
  47. 47.
    Zhang DX, Yi FX, Zou AP, Li PL (2002) Role of ceramide in TNF-alpha-induced impairment of endothelium-dependent vasorelaxation in coronary arteries. Am J Physiol Heart Circ Physiol 283:H1785–1794PubMedGoogle Scholar
  48. 48.
    Scheel-Toellner D, Wang K, Craddock R, et al (2004) Reactive oxygen species limit neutrophil life span by activating death receptor signaling. Blood 104:2557–2564CrossRefPubMedGoogle Scholar
  49. 49.
    Lightle S, Tosheva R, Lee A, et al (2003) Elevation of ceramide in serum lipoproteins during acute phase response in humans and mice: role of serine-palmitoyl transferase. Arch Biochem Biophys 419:120–128CrossRefPubMedGoogle Scholar
  50. 50.
    Langmann T, Buechler C, Ries S, et al (1999) Transcription factors Sp1 and AP-2 mediate induction of acid sphingomyelinase during monocytic differentiation. J Lipid Res 40:870–880PubMedGoogle Scholar
  51. 51.
    Mathias S, Pena LA, Kolesnick RN (1998) Signal transduction of stress via ceramide. Biochem J 335:465–480PubMedGoogle Scholar
  52. 52.
    Drobnik W, Liebisch G, Audebert FX, et al (2003) Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res 44:754–761CrossRefPubMedGoogle Scholar
  53. 53.
    Delogu G, Famularo G, Amati F, et al (1999) Ceramide concentrations in septic patients: a possible marker of multiple organ dysfunction syndrome. Crit Care Med 27:2413–2417CrossRefPubMedGoogle Scholar
  54. 54.
    Takahashi T, Abe T, Sato T, et al (2002) Elevated sphingomyelinase and hypercytokinemia in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 24:401–404CrossRefPubMedGoogle Scholar
  55. 55.
    Kornhuber J, Medlin A, Bleich S, et al (2005) High activity of acid sphingomyelinase in major depression. J Neural Transm 112:1583–1590CrossRefPubMedGoogle Scholar
  56. 56.
    Sathishkumar S, Boyanovsky B, Karakashian AA, et al (2005) Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: implications for endothelial apoptosis. Cancer Biol Ther 4:979–986PubMedCrossRefGoogle Scholar
  57. 57.
    Goggel R, Winoto-Morbach S, Vielhaber G, et al (2004) PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med 10:155–160CrossRefPubMedGoogle Scholar
  58. 58.
    Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM (2002) The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 30: S294–301CrossRefPubMedGoogle Scholar
  59. 59.
    Garcia-Ruiz C, Colell A, Mari M, et al (2003) Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest 111:197–208PubMedGoogle Scholar
  60. 60.
    Llacuna L, Mari M, Garcia-Ruiz C, Fernandez-Checa JC, Morales A (2006) Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology 44: 561–572CrossRefPubMedGoogle Scholar
  61. 61.
    Romiti E, Vasta V, Meacci E, et al (2000) Characterization of sphingomyelinase activity released by thrombin-stimulated platelets. Mol Cell Biochem 205:75–81CrossRefPubMedGoogle Scholar
  62. 62.
    Bhatia R, Matsushita K, Yamakuchi M, Morrell CN, Cao W, Lowenstein CJ (2004) Ceramide triggers Weibel-Palade body exocytosis. Circ Res 95:319–324CrossRefPubMedGoogle Scholar
  63. 63.
    Loidl A, Sevcsik E, Riesenhuber G, Deigner HP, Hermetter A (2003) Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. J Biol Chem 278:32921–32928CrossRefPubMedGoogle Scholar
  64. 64.
    Loidl A, Claus R, Ingolic E, Deigner HP, Hermetter A (2004) Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells. Biochim Biophys Acta 1690:150–158PubMedGoogle Scholar
  65. 65.
    Claus RA, Wustholz A, Muller S, et al (2005) Synthesis and antiapoptotic activity of a novel analogue of the neutral sphingomyelinase inhibitor scyphostatin. Chembiochem 6:726–737CrossRefPubMedGoogle Scholar
  66. 66.
    Arenz C, Thutewohl M, Block O, Waldmann H, Altenbach HJ, Giannis A (2001) Manumycin A and its analogues are irreversible inhibitors of neutral sphingomyelinase. Chembiochem 2:141–143CrossRefPubMedGoogle Scholar
  67. 67.
    Yokomatsu T, Takechi H, Akiyama T, et al (2001) Synthesis and evaluation of a difluoromethylene analogue of sphingomyelin as an inhibitor of sphingomyelinase. Bioorg Med Chem Lett 11: 1277–12780CrossRefPubMedGoogle Scholar
  68. 68.
    Kolzer M, Werth N, Sandhoff K (2004) Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559:96–98CrossRefPubMedGoogle Scholar
  69. 69.
    Brinkmann V, Lynch KR (2002) FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr Opin Immunol 14:569–575CrossRefPubMedGoogle Scholar
  70. 70.
    Hassler DF, Laethem RM, Smith GK (2000) A high throughput sphingomyelinase assay. Methods Enzymol 311:176–184CrossRefPubMedGoogle Scholar
  71. 71.
    Olivera A, Spiegel S (1998) Sphingosine kinase. Assay and product analysis. Methods Mol Biol 105:233–242PubMedGoogle Scholar
  72. 72.
    Bartelsen O, Lansmann S, Nettersheim M, Lemm T, Ferlinz K, Sandhoff K (1998) Expression of recombinant human acid sphingomyelinase in insect Sf21 cells: purification, processing and enzymatic characterization. J Biotechnol 63:29–40CrossRefPubMedGoogle Scholar
  73. 73.
    He X, Chen F, Dagan A, Gatt S, Schuchman EH (2003) A fluorescence-based, high-performance liquid chromatographic assay to determine acid sphingomyelinase activity and diagnose types A and B Niemann-Pick disease. Anal Biochem 314:116–120CrossRefPubMedGoogle Scholar
  74. 74.
    He X, Dagan A, Gatt S, Schuchman EH (2005) Simultaneous quantitative analysis of ceramide and sphingosine in mouse blood by naphthalene-2,3-dicarboxyaldehyde derivatization after hydrolysis with ceramidase. Anal Biochem 340:113–122CrossRefPubMedGoogle Scholar
  75. 75.
    Liu B, Hannun YA (2000) Sphingomyelinase assay using radiolabeled substrate. Methods Enzymol 311:164–167CrossRefPubMedGoogle Scholar
  76. 76.
    Tomas M, Duran JM, Lazaro-Dieguez F, Babia T, Renau-Piqueras J, Egea G (2004) Fluorescent analogues of plasma membrane sphingolipids are sorted to different intracellular compartments in astrocytes; Harmful effects of chronic ethanol exposure on sphingolipid trafficking and metabolism. FEBS Lett 563:59–65CrossRefPubMedGoogle Scholar
  77. 77.
    Pagano RE, Chen CS (1998) Use of BODIPY-labeled sphingolipids to study membrane traffic along the endocytic pathway. Ann N Y Acad Sci 845:152–160CrossRefPubMedGoogle Scholar
  78. 78.
    Bielawski J, Szulc ZM, Hannun YA, Bielawska A (2006) Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods 39:82–91CrossRefPubMedGoogle Scholar
  79. 79.
    Merrill AH Jr, Sullards MC, Allegood JC, Kelly S, Wang E (2005) Sphingolipidomics: high-throughput, structure-specific, and quantitative analysis of sphingolipids by liquid chromatography tandem mass spectrometry. Methods 36:207–224CrossRefPubMedGoogle Scholar
  80. 80.
    Ogretmen B, Pettus BJ, Rossi MJ, et al (2002) Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. J Biol Chem 277:12960–12969CrossRefPubMedGoogle Scholar
  81. 81.
    Osawa Y, Uchinami H, Bielawski J, Schwabe RF, Hannun YA, Brenner DA (2005) Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha. J Biol Chem 280:27879–27887CrossRefPubMedGoogle Scholar
  82. 82.
    Birbes H, El Bawab S, Hannun YA, Obeid LM (2001) Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. Faseb J 15: 2669–2679CrossRefPubMedGoogle Scholar
  83. 83.
    Marchesini N, Luberto C, Hannun YA (2003) Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism. J Biol Chem 278:13775–13783CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2007

Authors and Affiliations

  • H. P. Deigner
    • 1
  • E. Gulbins
    • 2
  • R. A. Claus
    • 1
  1. 1.Department of Anesthesiology and Intensive Care MedicineUniversity Hospital Friedrich-Schiller- UniversityJenaGermany
  2. 2.Institute of Molecular BiologyUniversity DuisburgEssenGermany

Personalised recommendations