Skip to main content
SpringerLink
Log in

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

  • Short Communication
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  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):23722–23728

    Article  PubMed  CAS  Google Scholar 

  2. Takabe K, Paugh SW, Milstien S, Spiegel S (2008) “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 60(2):181–195

    Article  PubMed  CAS  Google Scholar 

  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):19513–19520

    Article  PubMed  CAS  Google Scholar 

  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):4193–4200

    Article  PubMed  CAS  Google Scholar 

  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):1454–1458

    Article  PubMed  CAS  Google Scholar 

  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):36865–36872

    Article  PubMed  CAS  Google Scholar 

  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):2649–2659

    Article  CAS  Google Scholar 

  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):346–349

    Article  PubMed  CAS  Google Scholar 

  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):355–360

    Article  PubMed  CAS  Google Scholar 

  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):1874–1878

    Article  PubMed  CAS  Google Scholar 

  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):2097–2103

    Article  PubMed  CAS  Google Scholar 

  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):2114–2121

    Article  PubMed  CAS  Google Scholar 

  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):5644–5648

    PubMed  CAS  Google Scholar 

  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):129–139

    Article  PubMed  CAS  Google Scholar 

  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):1787–1793

    Article  PubMed  CAS  Google Scholar 

  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):997–1012

    Article  PubMed  CAS  Google Scholar 

  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):2570–2579

    Article  PubMed  CAS  Google Scholar 

  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):82–91

    Article  PubMed  CAS  Google Scholar 

  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):143–152

    Article  PubMed  CAS  Google Scholar 

  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):35257–35262

    Article  PubMed  CAS  Google Scholar 

  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):12576–12583

    Article  PubMed  CAS  Google Scholar 

  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):75–87

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Microbiology and Immunology, 173 Ashley Avenue MSC 504 Room 203, Charleston, SC, 29425, USA

    DeAnna A. Baker

  2. Department of Medicine, 96 Jonathan Lucas Street, Suite 803, Charleston, SC, 29425, USA

    Lina M. Obeid & Gary S. Gilkeson

  3. Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street Suite 912, Charleston, SC, 29425, USA

    Jackie Eudaly & Gary S. Gilkeson

  4. Departments of Biochemistry and Molecular Biology, 173 Ashley Avenue, P.O. Box 250509, Charleston, SC, 29425, USA

    Lina M. Obeid

  5. Medical Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA

    Lina M. Obeid & Gary S. Gilkeson

  6. South Carolina College of Pharmacy/Pharmaceutical and Biomedical Sciences, 280 Calhoun Street HCC 617, Charleston, SC, 29425, USA

    Charles D. Smith

  7. Division of Rheumatology, Department of Medicine, Medical University of South Carolina, 114 Doughty Street, STB 425, Charleston, SC, 29425, USA

    Gary S. Gilkeson

Authors
  1. DeAnna A. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jackie Eudaly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charles D. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lina M. Obeid
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary S. Gilkeson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary S. Gilkeson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baker, D.A., Eudaly, J., Smith, C.D. et al. Impact of sphingosine kinase 2 deficiency on the development of TNF-alpha-induced inflammatory arthritis. Rheumatol Int 33, 2677–2681 (2013). https://doi.org/10.1007/s00296-012-2493-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-012-2493-2

Keywords

Search

Navigation