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Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II

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DOI: 10.4236/pp.2013.48090    3,275 Downloads   4,766 Views   Citations

ABSTRACT

Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

N. Seki, H. Kataoka, K. Sugahara, A. Fukunari and K. Chiba, "Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II," Pharmacology & Pharmacy, Vol. 4 No. 8, 2013, pp. 638-646. doi: 10.4236/pp.2013.48090.

References

[1] S. Mandala, R. Hajdu, J. Bergstrom, E. Quackenbush, J. Xie, J. Milligan, R. Thornton, G. J. Shei, D. Card, C. Keohane, M. Rosenbach, J. Hale, C. L. Lynch, K. Rupprecht, W. Parsons and H. Rosen, “Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists,” Science, Vol. 296, No. 5566, 2002, pp. 346-349. http://dx.doi.org/10.1126/science.1070238
[2] M. Matloubian, C. G. Lo, G. Cinamon, M. J. Lesneski, Y. Xu, V. Brinkmann, M. L. Allende, R. L. Proia and J. G. Cyster, “Lymphocyte Egress from Thymus and Peripheral Lymphoid Organs Is Dependent on S1P Receptor 1,” Nature, Vol. 427, No. 6972, 2004, pp. 355-360.
http://dx.doi.org/10.1038/nature02284
[3] J. G. Cyster, “Chemokines, Sphingosine-1-Phosphate, and Cell Migration in Secondary Lymphoid Organs,” Annual Review of Immunology, Vol. 23, 2005, pp. 127-159.
http://dx.doi.org/10.1146/annurev.immunol.23.021704.115628
[4] C. G. Lo, Y. Xu, R. L. Proia and J. G. Cyster, “Cyclical Modulation of Sphingosine-1-Phosphate Receptor 1 Surface Expression during Lymphocyte Recirculation and Relationship to Lymphoid Organ Transit,” Journal of Experimental Medicine, Vol. 201, No. 2, 2005, pp. 291-301. http://dx.doi.org/10.1084/jem.20041509
[5] T. H. Pham, T. Okada, M. Matloubian, C. G. Lo and J. G. Cyster, “S1P1 Receptor Signaling Overrides Retention Mediated by G Alpha i-Coupled Receptors to Promote T Cell Egress,” Immunity, Vol. 28, No. 1, 2008, pp. 122-133. http://dx.doi.org/10.1016/j.immuni.2007.11.017
[6] K. Adachi, T. Kohara, N. Nakao, M. Arita, K. Chiba, T. Mishina, S. Sasaki and T. Fujita, “Design, Synthesis, and Structure Activity Relationships of 2-Substitued-2-Amino-1, 3-Propanediols: Discovery of a Novel Immunosup-pressant, FTY720,” Bioorganic & Medicinal Chemistry Letters, Vol. 5, 1995, pp. 853-856.
http://dx.doi.org/10.1016/0960-894X(95)00127-F
[7] M. Kiuchi, K. Adachi, A. Tomatsu, M. Chino, S. Takeda, Y. Tanaka, Y. Maeda, N. Sato, N. Mitsutomi, K. Sugahara and K. Chiba, “Asymmetric Synthesis and Biological Evaluation of the Enantiomeric Isomers of the Immunosuppressive FTY720-Phosphate,” Bioorganic and Medicinal Chemistry, Vol. 13, No. 2, 2005, pp. 425-432.
http://dx.doi.org/10.1016/j.bmc.2004.10.008
[8] K. Chiba, “FTY720, a New Class of Immunomodulator, Inhibits Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus by Agonistic Activity at Sphingosine 1-Phosphate Receptors,” Pharmacology and Therapeutics, Vol. 108, No. 3, 2005, pp. 308-319.
http://dx.doi.org/10.1016/j.pharmthera.2005.05.002
[9] K. Chiba, H. Matsuyuki, Y. Maeda and K. Sugahara, “Role of Sphingosine 1-Phosphate Receptor Type 1 in Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus,” Cellular & Molecular Immunology, Vol. 3, No. 1, 2006, pp. 11-19.
[10] Y. Maeda, H. Matsuyuki, K. Shimano, H. Kataoka, K. Sugahara and K. Chiba, “Migration of CD4 T Cells and Dendritic Cells toward Sphingosine 1-Phosphate (S1P) Is Mediated by Different Receptor Subtypes: S1P Regulates the Functions of Murine Mature Dendritic Cells via S1P Receptor Type 3,” Journal of Immunology, Vol. 178, No. 6, 2007, pp. 3437-3446.
[11] S. Thangada, K. M. Khanna, V. A. Blaho, M. L. Oo, D. S. Im, C. Guo, L. Lefrancois and T. Hla, “Cell-Surface Residence of Sphingosine 1-Phosphate Receptor 1 on Lymphocytes Determines Lymphocyte Egress Kinetics,” Journal of Experimental Medicine, Vol. 207, No. 7, 2010, pp. 1475-1483. http://dx.doi.org/10.1084/jem.20091343
[12] F. Mullershausen, F. Zecri, C. Cetin, A. Billich, D. Guerini and K. Seuwen, “Persistent Signaling Induced by FTY720-Phosphate Is Mediated by Internalized S1P1 Receptors,” Nature Chemical Biology, Vol. 5, No. 6, 2009, pp. 428-434.
http://dx.doi.org/10.1038/nchembio.173
[13] M. L. Oo, S. Thangada, M. T. Wu, C. H. Liu, T. L. Macdonald, K. R. Lynch, C. Y. Lin and T. Hla, “Immunosuppressive and Anti-Angiogenic Sphingosine 1-Phosphate Receptor-1 Agonists Induce Ubiquitinylation and Proteasomal Degradation of the Receptor,” Journal of Biological Chemistry, Vol. 282, No. 12, 2007, pp. 9082-9089.
http://dx.doi.org/10.1074/jbc.M610318200
[14] D. A. Hafler, “Multiple Sclerosis,” Journal of Clinical Investigation, Vol. 113, No. 6, 2004, pp. 788-794.
http://dx.doi.org/10.1172/JCI21357
[15] V. K. Kuchroo, A. C. Anderson, H. Waldner, M. Munder, E. Bettelli and L. B. Nicholson, “T Cell Response in Experimental Autoimmune Encephalomyelitis (EAE): Role of Self and Cross-Reactive Antigens in Shaping, Tuning, and Regulating the Autopathogenic T Cell Repertoire,” Annual Review of Immunology, Vol. 20, 2002, pp. 101-123.
http://dx.doi.org/10.1146/annurev.immunol.20.081701.141316
[16] R. Martin and H. F. McFarland, “Immunological Aspects of Experimental Allergic Encephalomyelitis and Multiple Sclerosis,” Critical Reviews in Clinical Laboratory Sciences, Vol. 32, No. 2, 1995, pp. 121-182.
http://dx.doi.org/10.3109/10408369509084683
[17] L. Steinman, “Assessment of Animal Models for MS and Demyelinating Disease in the Design of rational Therapy,” Neuron, Vol. 24, No. 3, 1999, pp. 511-514.
http://dx.doi.org/10.1016/S0896-6273(00)81107-1
[18] M. Fujino, N. Funeshima, Y. Kitazawa, H. Kimura, H. Amemiya, S. Suzuki and X. K. Li, “Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment,” Journal of Pharmacology and Experimental Therapeutics, Vol. 305, No. 1, 2003, pp. 70-77. http://dx.doi.org/10.1124/jpet.102.045658
[19] M. Webb, C. S. Tham, F. F. Lin, K. Lariosa-Willingham, N. Yu, J. Hale, S. Mandala, J. Chun and T. S. Rao, “Sphingosine 1-Phosphate Receptor Agonists Attenuate Relapsing-Remitting Experimental Autoimmune Encephalitis in SJL Mice,” Journal of Neuroimmunology, Vol. 153, No. 1-2, 2004, pp. 108-121.
http://dx.doi.org/10.1016/j.jneuroim.2004.04.015
[20] H. Kataoka, K. Sugahara, K. Shimano, K. Teshima, M. Koyama, A. Fukunari and K. Chiba, “FTY720, Sphingosine 1-Phosphate Receptor Modulator, Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibition of T Cell Infiltration,” Cellular & Molecular Immunology, Vol. 2, No. 6, 2005, pp. 439-448.
[21] C. A. Foster, L. M. Howard, A. Schweitzer, E. Persohn, P. C. Hiestand, B. Balatoni, R. Reuschel, C. Beerli, M. Schwartz and A. Billich, “Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis,” Journal of Pharmacology and Experimental Therapeutics, Vol. 323, No. 2, 2007, pp. 469-475.
http://dx.doi.org/10.1124/jpet.107.127183
[22] B. Balatoni, M. K. Storch, E. M. Swoboda, V. Schonborn, A. Koziel, G. N. Lambrou, P. C. Hiestand, R. Weissert and C. A. Foster, “FTY720 Sustains and Restores Neuronal Function in the DA Rat Model of MOG-Induced Experimental Autoimmune Encephalomyelitis,” Brain Research Bulletin, Vol. 74, No. 5, 2007, pp. 307-316.
http://dx.doi.org/10.1016/j.brainresbull.2007.06.023
[23] D. Papadopoulos, J. Rundle, R. Patel, I. Marshall, J. Stretton, R. Eaton, J. C. Richardson, M. I. Gonzalez, K. L. Philpott and R. Reynolds, “FTY720 Ameliorates MOGInduced Experimental Autoimmune Encephalomyelitis by Suppressing Both Cellular and Humoral Immune Responses,” Journal of Neuroscience Research, Vol. 88, No. 2, 2010, pp. 346-359. http://dx.doi.org/10.1002/jnr.22196
[24] K. Chiba, H. Kataoka, N. Seki, K. Shimano, M. Koyama, A. Fukunari, K. Sugahara and T. Sugita, “Fingolimod (FTY720), Sphingosine 1-Phosphate Receptor Modulator, Shows Superior Efficacy as Compared with InterferonBeta in Mouse Experimental Autoimmune Encephalomyelitis,” International Immunopharmacology, Vol. 11, No. 3, 2011, pp. 366-372.
http://dx.doi.org/10.1016/j.intimp.2010.10.005
[25] J. W. Choi, S. E. Gardell, D. R. Herr, R. Rivera, C. W. Lee, K. Noguchi, S. T. Teo, Y. C. Yung, M. Lu, G. Kennedy and J. Chun, “FTY720 (Fingolimod) Efficacy in an Animal Model of Multiple Sclerosis Requires Astrocyte Sphingosine 1-Phosphate Receptor 1 (S1P1) Modulation,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 2, 2011, pp. 751-756. http://dx.doi.org/10.1073/pnas.1014154108
[26] M. G. Sanna, J. Liao, E. Jo, C. Alfonso, M. Y. Ahn, M. S. Peterson, B. Webb, S. Lefebvre, J. Chun, N. Gray and H. Rosen, “Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate,” Journal of Biological Chemistry, Vol. 279, No. 14, 2004, pp. 13839-13848.
http://dx.doi.org/10.1074/jbc.M311743200
[27] M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley and B. Stockinger, “TGFbeta in the Context of an Inflammatory Cytokine Milieu Supports de Novo Differentiation of IL-17-Producing T Cells,” Immunity, Vol. 24, No. 2, 2006, pp. 179-189.
http://dx.doi.org/10.1016/j.immuni.2006.01.001
[28] R. O. Carlson and S. H. Aschmies, “Tyrosine Kinase Activity Is Essential for Interleukin-1 Beta—Stimulated Production of Interleukin-6 in U373 Human Astrocytoma Cells,” Journal of Neurochemistry, Vol. 65, No. 6, 1995, pp. 2491-2499.
http://dx.doi.org/10.1046/j.1471-4159.1995.65062491.x
[29] C. G. Jung, H. J. Kim, V. E. Miron, S. Cook, T. E. Kennedy, C. A. Foster, J. P. Antel and B. Soliven, “Functional Consequences of S1P Receptor Modulation in Rat Oligodendroglial Lineage Cells,” Glia, Vol. 55, No. 16, 2007, pp. 1656-1667.
http://dx.doi.org/10.1002/glia.20576
[30] H. Matsuyuki, Y. Maeda, K. Yano, K. Sugahara, K. Chiba, T. Kohno and Y. Igarashi, “Involvement of Sphingosine 1-Phosphate (S1P) Receptor Type 1 and Type 4 in Migratory Response of Mouse T Cells toward S1P,” Cellular & Molecular Immunology, Vol. 3, No. 6, 2006, pp. 429-437.
[31] C. Wu, S. Y. Leong, C. S. Moore, Q. L. Cui, P. Gris, L. P. Bernier, T. A. Johnson, P. Seguela, T. E. Kennedy, A. Bar-Or and J. P. Antel, “Dual Effects of Daily FTY720 on Human Astrocytes in Vitro: Relevance for Neuroinflammation,” Journal of Neuroinflammation, Vol. 10, 2013, p. 41.
http://dx.doi.org/10.1186/1742-2094-10-41
[32] L. Izikson, R. S. Klein, I. F. Charo, H. L. Weiner and A. D. Luster, “Resistance to Experimental Autoimmune Encephalomyelitis in Mice Lacking the CC Chemokine Receptor (CCR)2,” Journal of Experimental Medicine, Vol. 192, No. 7, 2000, pp. 1075-1080.
http://dx.doi.org/10.1084/jem.192.7.1075
[33] E. B. Samoilova, J. L. Horton, B. Hilliard, T. S. Liu and Y. Chen, “IL-6-Deficient Mice Are Resistant to Experimental Autoimmune Encephalomyelitis: Roles of IL-6 in the Activation and Differentiation of Autoreactive T Cells,” Journal of Immunology, Vol. 161, No. 12, 1998, pp. 6480-6486.
[34] Y. Okuda, S. Sakoda, C. C. Bernard, H. Fujimura, Y. Saeki, T. Kishimoto and T. Yanagihara, “IL-6-Deficient Mice Are Resistant to the Induction of Experimental Autoimmune Encephalomyelitis Provoked by Myelin Oligodendrocyte Glycoprotein,” International Immunology, Vol. 10, No. 5, 1998, pp. 703-708.
http://dx.doi.org/10.1093/intimm/10.5.703
[35] R. S. Klein, L. Izikson, T. Means, H. D. Gibson, E. Lin, R. A. Sobel, H. L. Weiner and A. D. Luster, “IFN-Inducible Protein 10/CXC Chemokine Ligand 10-Independent Induction of Experimental Autoimmune Encephalomyelitis,” Journal of Immunology, Vol. 172, No. 1, 2004, pp. 550-559.
[36] M. Giralt, R. Ramos, A. Quintana, B. Ferrer, M. Erta, M. Castro-Freire, G. Comes, E. Sanz, M. Unzeta, P. Pifarre, A. Garcia, I. L. Campbell and J. Hidalgo, “Induction of Atypical EAE Mediated by Transgenic Production of IL-6 in Astrocytes in the Absence of Systemic IL-6,” Glia, Vol. 61, No. 4, pp. 587-600.
http://dx.doi.org/10.1002/glia.22457
[37] S. L. Carter, M. Muller, P. M. Manders and I. L. Campbell, “Induction of the Genes for Cxcl9 and Cxcl10 Is Dependent on IFN-Gamma but Shows Differential Cellular Expression in Experimental Autoimmune Encephalomyelitis and by Astrocytes and Microglia in Vitro,” Glia, Vol. 55, No. 16, 2007, pp. 1728-1739.
http://dx.doi.org/10.1002/glia.20587
[38] R. Van Doorn, J. Van Horssen, D. Verzijl, M. Witte, E. Ronken, B. Van Het Hof, K. Lakeman, C. D. Dijkstra, P. Van Der Valk, A. Reijerkerk, A. E. Alewijnse, S. L. Peters and H. E. De Vries, “Sphingosine 1-Phosphate Receptor 1 and 3 Are Upregulated in Multiple Sclerosis Lesions,” Glia, Vol. 58, No. 12, 2010, pp. 1465-1476.
[39] A. Kimura, T. Ohmori, R. Ohkawa, S. Madoiwa, J. Mimuro, T. Murakami, E. Kobayashi, Y. Hoshino, Y. Yatomi and Y. Sakata, “Essential Roles of Sphingosine 1-Phosphate/S1P1 Receptor Axis in the Migration of Neural Stem Cells toward a Site of Spinal Cord Injury,” Stem Cells, Vol. 25, No. 1, 2007, pp. 115-124.
http://dx.doi.org/10.1634/stemcells.2006-0223
[40] K. Lieb, C. Kaltschmidt, B. Kaltschmidt, P. A. Baeuerle, M. Berger, J. Bauer and B. L. Fiebich, “Interleukin-1 Beta Uses Common and Distinct Signaling Pathways for Induction of the Interleukin-6 and Tumor Necrosis Factor Alpha Genes in the Human Astrocytoma Cell Line U373,” Journal of Neurochemistry, Vol. 66, No. 4, 1996, pp. 1496-1503.
http://dx.doi.org/10.1046/j.1471-4159.1996.66041496.x
[41] H. L. Hsieh, C. C. Sun, C. B. Wu, C. Y. Wu, W. H. Tung, H. H. Wang and C. M. Yang, “Sphingosine 1-Phosphate Induces EGFR Expression via Akt/NF-kappaB and ERK/ AP-1 Pathways in Rat Vascular Smooth Muscle Cells,” Journal of Cellular Biochemistry, Vol. 103, No. 6, 2008, pp. 1732-1746.
http://dx.doi.org/10.1002/jcb.21563

  
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