Advertisement

Inflammation Research

, Volume 66, Issue 6, pp 535–545 | Cite as

Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves’ orbitopathy

  • Yuri Seo
  • Min Kyung Chae
  • Sol Ah Han
  • Eun Jig Lee
  • Joon H. LeeEmail author
  • Jin Sook YoonEmail author
Original Research Paper

Abstract

Objective

Graves’ orbitopathy (GO) is initiated by excessive amount of various inflammatory mediators produced by orbital fibroblasts. This study aimed to assess the crucial role of sphingosine-1-phosphate (S1P) in the inflammatory process of GO.

Methods

Orbital adipose/connective tissue samples were obtained from 10 GO patients and 10 normal control individuals during surgery. Primary orbital fibroblast culture was done. After the expression of S1P receptors and sphingosine kinase (SphK) was assessed with the treatment of interleukin (IL)-1β, we evaluated the expression of pro-inflammatory factors [intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and IL-6] after treating S1P. S1P receptor antagonists and SphK 1 inhibitor were pretreated and the expression of the pro-inflammatory factors was assessed.

Results

IL-1β exacerbated the inflammatory process by enhancing the expression of S1P receptors and SphK in GO orbital fibroblasts. IL-1β also induced the expressions of ICAM-1, COX-2, and IL-6 in GO orbital fibroblasts, and these expressions were effectively inhibited by S1P receptor antagonists and SphK1 inhibitor.

Conclusion

S1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO.

Keywords

Graves’ orbitopathy Orbital fibroblasts Inflammation Sphingosine-1-phosphate S1P receptor antagonist 

Notes

Compliance with ethical standards

Conflict of interest

The authors have nothing to disclose.

Grant

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2007190) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, Republic of Korea (Grant Number: HI14C1324).

References

  1. 1.
    Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminoglycans, and diseases the thyroid. Endocr Rev. 1989;10:366–91.CrossRefPubMedGoogle Scholar
  2. 2.
    Bahn RS. Graves’ ophthalmopathy. N Engl J Med (Baltim). 2010;362:726–38.CrossRefGoogle Scholar
  3. 3.
    Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves’ ophthalmopathy. Exp Eye Res. 2016;142:83–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Rundle F, Wilson C. Development and course of exophthalmos and ophthalmoplegia in Graves’ disease with special reference to the effect of thyroidectomy. Clin Sci. 1945;5:177.PubMedGoogle Scholar
  5. 5.
    Rao R, MacIntosh PW, Yoon MK, Lefebvre DR. Current trends in the management of thyroid eye disease. Curr Opin Ophthalmol. 2015;26:484–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Pyne NJ, Ohotski J, Bittman R, Pyne S. The role of sphingosine 1-phosphate in inflammation and cancer. Adv Biol Regul. 2014;54:121–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4:397–407.CrossRefPubMedGoogle Scholar
  8. 8.
    Billich A, Bornancin F, Mechtcheriakova D, Natt F, Huesken D, Baumruker T. Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: function in cell survival and IL-1β and TNF-α induced production of inflammatory mediators. Cell Signal. 2005;17:1203–17.CrossRefPubMedGoogle Scholar
  9. 9.
    Florey O, Haskard DO. Sphingosine 1-phosphate enhances Fcγ receptor-mediated neutrophil activation and recruitment under flow conditions. J Immunol. 2009;183:2330–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Milara J, Mata M, Mauricio MD, Donet E, Morcillo EJ, Cortijo J. Sphingosine-1-phosphate increases human alveolar epithelial IL-8 secretion, proliferation and neutrophil chemotaxis. Eur J Pharmacol. 2009;609:132–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Kitano M, Hla T, Sekiguchi M, Kawahito Y, Yoshimura R, Miyazawa K, Iwasaki T, Sano H, Saba JD, Tam YY. Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression. Arthritis Rheum. 2006;54:742–53.CrossRefPubMedGoogle Scholar
  12. 12.
    Watson L, Tullus K, Marks S, Holt R, Pilkington C, Beresford M. Increased serum concentration of sphingosine-1-phosphate in juvenile-onset systemic lupus erythematosus. J Clin Immunol. 2012;32:1019–25.CrossRefPubMedGoogle Scholar
  13. 13.
    Snider AJ. Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease. Int J Clin Rheumatol. 2013;8:453–63.CrossRefGoogle Scholar
  14. 14.
    Snider AJ, Kawamori T, Bradshaw SG, Orr KA, Gilkeson GS, Hannun YA, Obeid LM. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. Fed Am Soc Exp Biol. 2009;23:143–52.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kim SE, Lee JH, Chae MK, Lee EJ, Yoon JS. The role of Sphingosine-1-phosphate in adipogenesis of Graves’ orbitopathy role of S1P in adipogenesis of Graves’ orbitopathy. Investig Ophthalmol Vis Sci. 2016;57:301–11.CrossRefGoogle Scholar
  16. 16.
    Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A. Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008;158:273–85.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhao L-Q, Wei R-L, Cheng J-W, Cai J-P, Li Y. The expression of intercellular adhesion molecule-1 induced by CD40-CD40L ligand signaling in orbital fibroblasts in patients with Graves’ ophthalmopathy. Investig Ophthalmol Vis Sci. 2010;51:4652–60.CrossRefGoogle Scholar
  18. 18.
    Cawood T, Moriarty P, O’Farrelly C, O’shea D. Smoking and thyroid-associated ophthalmopathy: a novel explanation of the biological link. J Clin Endocrinol Metab. 2007;92:59–64.CrossRefPubMedGoogle Scholar
  19. 19.
    Han R, Smith TJ. T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1β in orbital fibroblasts: implications for the pathogenesis of thyroid-associated ophthalmopathy. Endocrinology. 2006;147:13–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Carey MA, Germolec DR, Langenbach R, Zeldin DC. Cyclooxygenase enzymes in allergic inflammation and asthma. Prostaglandins, Leukot Essent Fatty Acids. 2003;69:157–62.CrossRefGoogle Scholar
  21. 21.
    Jyonouchi SC, Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathy. Thyroid. 2001;11:929–34.CrossRefPubMedGoogle Scholar
  22. 22.
    Hwang CJ, Afifiyan N, Sand D, Naik V, Said J, Pollock SJ, Chen B, Phipps RP, Goldberg RA, Smith TJ. Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1. Investig Ophthalmol Vis Sci. 2009;50:2262–8.CrossRefGoogle Scholar
  23. 23.
    Cheng AM, Yin HY, Chen A, Liu Y-W, Chuang M-C, He H, Tighe S, Sheha H, Liao S-L. Celecoxib and pioglitazone as potential therapeutics for regulating TGF-β-Induced hyaluronan in dysthyroid myopathy. Investig Ophthalmol Vis Sci. 2016;57:1951–9.CrossRefGoogle Scholar
  24. 24.
    Kumar S, Schiefer R, Coenen MJ, Bahn RS. A stimulatory thyrotropin receptor antibody (M22) and thyrotropin increase interleukin-6 expression and secretion in Graves’ orbital preadipocyte fibroblasts. Thyroid. 2010;20:59–65.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41:2502–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Hsu CK, Lee IT, Lin CC, Hsiao LD, Yang CM. Sphingosine-1-phosphate mediates COX-2 expression and PGE2/IL-6 secretion via c-Src-dependent AP-1 activation. J Cell Physiol. 2015;230:702–15.CrossRefPubMedGoogle Scholar
  27. 27.
    Lin C-C, Yang C-C, Cho R-L, Wang C-Y, Hsiao L-D, Yang C-M. Sphingosine 1-phosphate-induced ICAM-1 expression via NADPH oxidase/ROS-dependent NF-κB cascade on human pulmonary alveolar epithelial cells. Front Pharmacol. 2016;7.Google Scholar
  28. 28.
    Imeri F, Blanchard O, Jenni A, Schwalm S, Wünsche C, Zivkovic A, Stark H, Pfeilschifter J, Huwiler A. FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase. Naunyn-Schmiedeberg’s Arch Pharmacol. 2015;388:1283–92.CrossRefGoogle Scholar
  29. 29.
    Fan L, Yan H. FTY720 Attenuates retinal inflammation and protects blood–retinal barrier in diabetic RatsFTY720 attenuates retinal inflammation and protects BRB. Investig Ophthalmol Vis Sci. 2016;57:1254–63.CrossRefGoogle Scholar
  30. 30.
    Liu W, Liu B, Liu S, Zhang J, Lin S. Sphingosine-1-phosphate receptor 2 mediates endothelial cells dysfunction by PI3K-Akt pathway under high glucose condition. Eur J Pharmacol. 2016;776:19–25.CrossRefPubMedGoogle Scholar
  31. 31.
    Snider AJ, Ruiz P, Obeid LM, Oates JC. Inhibition of sphingosine kinase-2 in a murine model of lupus nephritis. PloS One. 2013;8:e53521.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS drugs. 2015;29:565–75.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pyne NJ, Pyne S. Sphingosine kinase 1 enables communication between melanoma cells and fibroblasts that provides a new link to metastasis. Oncogene. 2014;33:3361–3.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Department of Ophthalmology, Institute of Vision ResearchYonsei University College of MedicineSeoulSouth Korea
  2. 2.Kyunghee University College of MedicineSeoulSouth Korea
  3. 3.Department of Endocrinology, Institute of Endocrine ResearchYonsei University College of MedicineSeoulSouth Korea
  4. 4.Myunggok Eye Research Institute, Kim’s Eye HospitalKonyang University College of MedicineNonsanSouth Korea

Personalised recommendations