Rheumatology International

, Volume 33, Issue 10, pp 2677–2681 | Cite as

Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis

  • DeAnna A. Baker
  • Jackie Eudaly
  • Charles D. Smith
  • Lina M. Obeid
  • Gary S. Gilkeson
Short Communication


Sphingolipids are components of the plasma membrane whose metabolic manipulation is of interest as a potential therapeutic approach in a number of diseases. Sphingosine kinase 1 (SphK1), the major kinase that phosphorylates sphingosine to sphingosine-1-phosphate (S1P), was previously shown by our group and others to modulate inflammation in murine models of inflammatory arthritis, inflammatory bowel disease and asthma. Sphingosine kinase 2’s (SphK2) impact on inflammation is less well known, as variable results were reported depending on the disease model. A specific SphK2 inhibitor inhibited inflammatory arthritis in one model, while siRNA knockdown of SphK2 worsened arthritis in another. We previously demonstrated that SphK1 deficient mice are protected against development of hTNF-α-induced arthritis. To investigate the role of SphK2 in TNF-α-induced arthritis, we developed SphK2 deficient hTNF-α overexpressing mice and separately treated hTNF-α mice with ABC294640, a SphK2-specific inhibitor. Our data show that genetic inhibition of SphK2 did not significantly impact the severity or progression of inflammatory arthritis, while pharmacologic inhibition of SphK2 led to significantly more severe arthritis. Compared to vehicle-treated mice, ABC294640 treated mice also had less S1P in whole blood and inflamed joint tissue, although the differences were not significant. ABC294640 treatment did not affect SphK1 activity in the inflamed joint while little SphK2 activity was detected in the joint. We conclude that the differences in the inflammatory phenotype in genetic inhibition versus pharmacologic inhibition of SphK2 can be attributed to the amount of ABC294640 used in the experiments versus the impact of acute inhibition of SphK2 with ABC294640 versus genetically induced life-long SphK2 deficiency. Thus, inhibition of SphK2 appears to be proinflammatory in contrast to the clear anti-inflammatory effects of blocking SphK1. Therapies directed at this sphingosine kinase pathways will need to be specific in their targeting of sphingosine kinases.


Sphingosine kinase 2 Inflammatory arthritis Sphingolipids TNF 


  1. 1.
    Kohama T, Olivera A, Edsall L, Nagiec MM, Dickson R, Spiegel S (1998) Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 273(37):23722–23728PubMedCrossRefGoogle Scholar
  2. 2.
    Takabe K, Paugh SW, Milstien S, Spiegel S (2008) “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 60(2):181–195PubMedCrossRefGoogle Scholar
  3. 3.
    Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, Milstien S, Kohama T, Spiegel S (2000) Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 275(26):19513–19520PubMedCrossRefGoogle Scholar
  4. 4.
    Oskeritzian CA, Alvarez SE, Hait NC, Price MM, Milstien S, Spiegel S (2008) Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions. Blood 111(8):4193–4200PubMedCrossRefGoogle Scholar
  5. 5.
    Zemann B, Kinzel B, Muller M, Reuschel R, Mechtcheriakova D, Urtz N, Bornancin F, Baumruker T, Billich A (2006) Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood 107(4):1454–1458PubMedCrossRefGoogle Scholar
  6. 6.
    Kharel Y, Lee S, Snyder AH, Sheasley-O’neill SL, Morris MA, Setiady Y, Zhu R, Zigler MA, Burcin TL, Ley K, Tung KS, Engelhard VH, Macdonald TL, Pearson-White S, Lynch KR (2005) Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 280(44):36865–36872PubMedCrossRefGoogle Scholar
  7. 7.
    Lan YY, De Creus A, Colvin BL, Abe M, Brinkmann V, Coates PT, Thomson AW (2005) The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo. Am J Transpl 5(11):2649–2659CrossRefGoogle Scholar
  8. 8.
    Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296(5566):346–349PubMedCrossRefGoogle Scholar
  9. 9.
    Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427(6972):355–360PubMedCrossRefGoogle Scholar
  10. 10.
    Graeler M, Goetzl EJ (2002) Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J 16(14):1874–1878PubMedCrossRefGoogle Scholar
  11. 11.
    Lai WQ, Irwan AW, Goh HH, Melendez AJ, McInnes IB, Leung BP (2009) Distinct roles of sphingosine kinase 1 and 2 in murine collagen-induced arthritis. J Immunol 183(3):2097–2103PubMedCrossRefGoogle Scholar
  12. 12.
    Weigert A, Schiffmann S, Sekar D, Ley S, Menrad H, Werno C, Grosch S, Geisslinger G, Brune B (2009) Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype. Int J Cancer 125(9):2114–2121PubMedCrossRefGoogle Scholar
  13. 13.
    Samy ET, Meyer CA, Caplazi P, Langrish CL, Lora JM, Bluethmann H, Peng SL (2007) Cutting edge: modulation of intestinal autoimmunity and IL-2 signaling by sphingosine kinase 2 independent of sphingosine 1-phosphate. J Immunol 179(9):5644–5648PubMedGoogle Scholar
  14. 14.
    French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD (2010) Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther 333(1):129–139PubMedCrossRefGoogle Scholar
  15. 15.
    Chumanevich AA, Poudyal D, Cui X, Davis T, Wood PA, Smith CD, Hofseth LJ (2010) Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis 31(10):1787–1793PubMedCrossRefGoogle Scholar
  16. 16.
    Maines LW, Fitzpatrick LR, French KJ, Zhuang Y, Xia Z, Keller SN, Upson JJ, Smith CD (2008) Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 53(4):997–1012PubMedCrossRefGoogle Scholar
  17. 17.
    Baker DA, Barth J, Chang R, Obeid LM, Gilkeson GS (2010) Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-alpha-induced arthritis. J Immunol 185(4):2570–2579PubMedCrossRefGoogle Scholar
  18. 18.
    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(2):82–91PubMedCrossRefGoogle Scholar
  19. 19.
    Snider AJ, Kawamori T, Bradshaw SG, Orr KA, Gilkeson GS, Hannun YA, Obeid LM (2009) A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J 23(1):143–152PubMedCrossRefGoogle Scholar
  20. 20.
    Johnson KR, Becker KP, Facchinetti MM, Hannun YA, Obeid LM (2002) PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J Biol Chem 277(38):35257–35262PubMedCrossRefGoogle Scholar
  21. 21.
    Olivera A, Kohama T, Tu Z, Milstien S, Spiegel S (1998) Purification and characterization of rat kidney sphingosine kinase. J Biol Chem 273(20):12576–12583PubMedCrossRefGoogle Scholar
  22. 22.
    Fitzpatrick LR, Green C, Frauenhoffer EE, French KJ, Zhuang Y, Maines LW, Upson JJ, Paul E, Donahue H, Mosher TJ, Smith CD (2011) Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase. Inflammopharmacology 19(2):75–87PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2012

Authors and Affiliations

  • DeAnna A. Baker
    • 1
  • Jackie Eudaly
    • 3
  • Charles D. Smith
    • 6
  • Lina M. Obeid
    • 2
    • 4
    • 5
  • Gary S. Gilkeson
    • 2
    • 3
    • 5
    • 7
  1. 1.Departments of Microbiology and ImmunologyCharlestonUSA
  2. 2.Department of MedicineCharlestonUSA
  3. 3.Division of RheumatologyMedical University of South CarolinaCharlestonUSA
  4. 4.Departments of Biochemistry and Molecular BiologyCharlestonUSA
  5. 5.Medical Research ServiceRalph H. Johnson VA Medical CenterCharlestonUSA
  6. 6.South Carolina College of Pharmacy/Pharmaceutical and Biomedical SciencesCharlestonUSA
  7. 7.Division of Rheumatology, Department of MedicineMedical University of South CarolinaCharlestonUSA

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