Skip to main content

Advertisement

SpringerLink
Log in

Fingolimod Suppresses the Proinflammatory Status of Interferon-γ-Activated Cultured Rat Astrocytes

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Astroglia, the primary homeostatic cells of the central nervous system, play an important role in neuroinflammation. They act as facultative immunocompetent antigen-presenting cells (APCs), expressing major histocompatibility complex (MHC) class II antigens upon activation with interferon (IFN)-γ and possibly other proinflammatory cytokines that are upregulated in disease states, including multiple sclerosis (MS). We characterized the anti-inflammatory effects of fingolimod (FTY720), an established drug for MS, and its phosphorylated metabolite (FTY720-P) in IFN-γ-activated cultured rat astrocytes. The expression of MHC class II compartments, β2 adrenergic receptor (ADR-β2), and nuclear factor kappa-light-chain enhancer of activated B cells subunit p65 (NF-κB p65) was quantified in immunofluorescence images acquired by laser scanning confocal microscopy. In addition, MHC class II-enriched endocytotic vesicles were labeled by fluorescent dextran and their mobility analyzed in astrocytes subjected to different treatments. FTY720 and FTY720-P treatment significantly reduced the number of IFN-γ-induced MHC class II compartments and substantially increased ADR-β2 expression, which is otherwise small or absent in astrocytes in MS. These effects could be partially attributed to the observed decrease in NF-κB p65 expression, because the NF-κB signaling cascade is activated in inflammatory processes. We also found attenuated trafficking and secretion from dextran-labeled endo-/lysosomes that may hinder efficient delivery of MHC class II molecules to the plasma membrane. Our data suggest that FTY720 and FTY720-P at submicromolar concentrations mediate anti-inflammatory effects on astrocytes by suppressing their action as APCs, which may further downregulate the inflammatory process in the brain, constituting the therapeutic effect of fingolimod in MS.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61(12):1939–1958. https://doi.org/10.1002/glia.22575

    Article  PubMed  PubMed Central  Google Scholar 

  2. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215

    Article  CAS  PubMed  Google Scholar 

  3. Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T (2003) Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 278(48):47408–47415. https://doi.org/10.1074/jbc.M307687200

    Article  CAS  PubMed  Google Scholar 

  4. Bouvier M, Collins S, O'Dowd BF, Campbell PT, de Blasi A, Kobilka BK, MacGregor C, Irons GP et al (1989) Two distinct pathways for cAMP-mediated down-regulation of the beta 2-adrenergic receptor. Phosphorylation of the receptor and regulation of its mRNA level. J Biol Chem 264(28):16786–16792

    CAS  PubMed  Google Scholar 

  5. Boyle EA, McGeer PL (1990) Cellular immune response in multiple sclerosis plaques. Am J Pathol 137(3):575–584

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, Ivanov D, Nathanson L et al (2009) Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol 182(5):2628–2640. https://doi.org/10.4049/jimmunol.0802954

    Article  CAS  PubMed  Google Scholar 

  7. Brinkmann V (2009) FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 158(5):1173–1182. https://doi.org/10.1111/j.1476-5381.2009.00451.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brown AM, Baltan Tekkök S, Ransom BR (2004) Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochem Int 45(4):529–536. https://doi.org/10.1016/j.neuint.2003.11.005

    Article  CAS  PubMed  Google Scholar 

  9. Bunbury A, Potolicchio I, Maitra R, Santambrogio L (2009) Functional analysis of monocyte MHC class II compartments. FASEB J 23(1):164–171. https://doi.org/10.1096/fj.08-109439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T et al (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622. https://doi.org/10.1373/clinchem.2008.112797

    Article  CAS  PubMed  Google Scholar 

  11. Bö L, Mörk S, Kong PA, Nyland H, Pardo CA, Trapp BD (1994) Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J Neuroimmunol 51(2):135–146

    Article  PubMed  Google Scholar 

  12. Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC, Hafler DA (2015) Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci Transl Med 7(287):287ra274. https://doi.org/10.1126/scitranslmed.aaa8038

    Article  CAS  Google Scholar 

  13. Chan D, Binks S, Nicholas JM, Frost C, Cardoso MJ, Ourselin S, Wilkie D, Nicholas R et al (2017) Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol 16(8):591–600. https://doi.org/10.1016/S1474-4422(17)30113-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 383(9936):2213–2221. https://doi.org/10.1016/S0140-6736(13)62242-4

    Article  CAS  PubMed  Google Scholar 

  15. Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, Teo ST, Yung YC et al (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 108(2):751–756. https://doi.org/10.1073/pnas.1014154108

    Article  PubMed  Google Scholar 

  16. Chow A, Toomre D, Garrett W, Mellman I (2002) Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418(6901):988–994. https://doi.org/10.1038/nature01006

    Article  CAS  PubMed  Google Scholar 

  17. Chun J, Brinkmann V (2011) A mechanistically novel, first oral therapy for multiple sclerosis: The development of fingolimod (FTY720, Gilenya). Discov Med 12(64):213–228

    PubMed  PubMed Central  Google Scholar 

  18. Chun J, Hartung HP (2010) Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 33(2):91–101. https://doi.org/10.1097/WNF.0b013e3181cbf825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, Farina C (2014) Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol 76(3):325–337. https://doi.org/10.1002/ana.24217

    Article  CAS  PubMed  Google Scholar 

  20. De Keyser J, Laureys G, Demol F, Wilczak N, Mostert J, Clinckers R (2010) Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis. Neurochem Int 57(4):446–450. https://doi.org/10.1016/j.neuint.2010.02.012

    Article  CAS  PubMed  Google Scholar 

  21. De Keyser J, Mostert JP, Koch MW (2008) Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci 267(1–2):3–16. https://doi.org/10.1016/j.jns.2007.08.044

    Article  CAS  PubMed  Google Scholar 

  22. De Keyser J, Wilczak N, Leta R, Streetland C (1999) Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors. Neurology 53(8):1628–1633

    Article  PubMed  Google Scholar 

  23. De Keyser J, Zeinstra E, Frohman E (2003) Are astrocytes central players in the pathophysiology of multiple sclerosis? Arch Neurol 60(1):132–136

    Article  PubMed  Google Scholar 

  24. De Keyser J, Zeinstra E, Wilczak N (2004) Astrocytic beta2-adrenergic receptors and multiple sclerosis. Neurobiol Dis 15(2):331–339. https://doi.org/10.1016/j.nbd.2003.10.012

    Article  CAS  PubMed  Google Scholar 

  25. Dong JH, Chen X, Cui M, Yu X, Pang Q, Sun JP (2012) β2-adrenergic receptor and astrocyte glucose metabolism. J Mol Neurosci 48(2):456–463. https://doi.org/10.1007/s12031-012-9742-4

    Article  CAS  PubMed  Google Scholar 

  26. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145. https://doi.org/10.1016/j.it.2007.01.005

    Article  CAS  PubMed  Google Scholar 

  27. Foster CA, Howard LM, Schweitzer A, Persohn E, Hiestand PC, Balatoni B, Reuschel R, Beerli C et al (2007) 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. J Pharmacol Exp Ther 323(2):469–475. https://doi.org/10.1124/jpet.107.127183

    Article  CAS  PubMed  Google Scholar 

  28. Frohman EM, Frohman TC, Dustin ML, Vayuvegula B, Choi B, Gupta A, van den Noort S, Gupta S (1989) The induction of intercellular adhesion molecule 1 (ICAM-1) expression on human fetal astrocytes by interferon-gamma, tumor necrosis factor alpha, lymphotoxin, and interleukin-1: relevance to intracerebral antigen presentation. J Neuroimmunol 23(2):117–124

    Article  CAS  PubMed  Google Scholar 

  29. Frohman EM, Monson NL, Lovett-Racke AE, Racke MK (2001) Autonomic regulation of neuroimmunological responses: implications for multiple sclerosis. J Clin Immunol 21(2):61–73

    Article  CAS  PubMed  Google Scholar 

  30. Frohman EM, Vayuvegula B, Gupta S, van den Noort S (1988) Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (Ia) antigen expression on cultured astrocytes via beta-2-adrenergic signal transduction mechanisms. Proc Natl Acad Sci U S A 85(4):1292–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fukuhara S, Simmons S, Kawamura S, Inoue A, Orba Y, Tokudome T, Sunden Y, Arai Y et al (2012) The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. J Clin Invest 122(4):1416–1426. https://doi.org/10.1172/JCI60746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9(6):393–407. https://doi.org/10.1038/nri2550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Guček A, Vardjan N, Zorec R (2012) Exocytosis in astrocytes: transmitter release and membrane signal regulation. Neurochem Res 37(11):2351–2363. https://doi.org/10.1007/s11064-012-0773-6

    Article  CAS  PubMed  Google Scholar 

  34. Hadcock JR, Wang HY, Malbon CC (1989) Agonist-induced destabilization of beta-adrenergic receptor mRNA. Attenuation of glucocorticoid-induced up-regulation of beta-adrenergic receptors. J Biol Chem 264(33):19928–19933

    CAS  PubMed  Google Scholar 

  35. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 26(1):6–17. https://doi.org/10.1002/mds.23455

    Article  PubMed  Google Scholar 

  36. Harder DR, Zhang C, Gebremedhin D (2002) Astrocytes function in matching blood flow to metabolic activity. News Physiol Sci 17:27–31

    CAS  PubMed  Google Scholar 

  37. Hayashi T, Morimoto C, Burks JS, Kerr C, Hauser SL (1988) Dual-label immunocytochemistry of the active multiple sclerosis lesion: major histocompatibility complex and activation antigens. Ann Neurol 24(4):523–531. https://doi.org/10.1002/ana.410240408

    Article  CAS  PubMed  Google Scholar 

  38. Hisano Y, Kobayashi N, Kawahara A, Yamaguchi A, Nishi T (2011) The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720. J Biol Chem 286(3):1758–1766. https://doi.org/10.1074/jbc.M110.171116

    Article  CAS  PubMed  Google Scholar 

  39. Hoffmann A, Baltimore D (2006) Circuitry of nuclear factor kappaB signaling. Immunol Rev 210:171–186. https://doi.org/10.1111/j.0105-2896.2006.00375.x

    Article  PubMed  Google Scholar 

  40. Horvat A, Zorec R, Vardjan N (2016) Adrenergic stimulation of single rat astrocytes results in distinct temporal changes in intracellular Ca(2+) and cAMP-dependent PKA responses. Cell Calcium 59(4):156–163. https://doi.org/10.1016/j.ceca.2016.01.002

    Article  CAS  PubMed  Google Scholar 

  41. Hosoda K, Fitzgerald LR, Vaidya VA, Feussner GK, Fishman PH, Duman RS (1995) Regulation of beta 2-adrenergic receptor mRNA and gene transcription in rat C6 glioma cells: effects of agonist, forskolin, and protein synthesis inhibition. Mol Pharmacol 48(2):206–211

    CAS  PubMed  Google Scholar 

  42. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C et al (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362(5):387–401. https://doi.org/10.1056/NEJMoa0909494

    Article  CAS  PubMed  Google Scholar 

  43. Khoury SJ, Healy BC, Kivisäkk P, Viglietta V, Egorova S, Guttmann CR, Wedgwood JF, Hafler DA et al (2010) A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Arch Neurol 67(9):1055–1061. https://doi.org/10.1001/archneurol.2010.222

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kim RH, Takabe K, Milstien S, Spiegel S (2009) Export and functions of sphingosine-1-phosphate. Biochim Biophys Acta 1791(7):692–696. https://doi.org/10.1016/j.bbalip.2009.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kobayashi N, Nishi T, Hirata T, Kihara A, Sano T, Igarashi Y, Yamaguchi A (2006) Sphingosine 1-phosphate is released from the cytosol of rat platelets in a carrier-mediated manner. J Lipid Res 47(3):614–621. https://doi.org/10.1194/jlr.M500468-JLR200

    Article  CAS  PubMed  Google Scholar 

  46. Kobayashi N, Yamaguchi A, Nishi T (2009) Characterization of the ATP-dependent sphingosine 1-phosphate transporter in rat erythrocytes. J Biol Chem 284(32):21192–21200. https://doi.org/10.1074/jbc.M109.006163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. La Mantia L, Tramacere I, Firwana B, Pacchetti I, Palumbo R, Filippini G (2016) Fingolimod for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev 4:CD009371. https://doi.org/10.1002/14651858.CD009371.pub2

    Article  PubMed  Google Scholar 

  48. Lee SC, Moore GR, Golenwsky G, Raine CS (1990) Multiple sclerosis: a role for astroglia in active demyelination suggested by class II MHC expression and ultrastructural study. J Neuropathol Exp Neurol 49(2):122–136

    Article  CAS  PubMed  Google Scholar 

  49. Leibowitz SM, Yan J (2016) NF-κB pathways in the pathogenesis of multiple sclerosis and the therapeutic implications. Front Mol Neurosci 9:84. https://doi.org/10.3389/fnmol.2016.00084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, Chui D, Yu AC (2011) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer's disease. Curr Alzheimer Res 8(1):67–80

    Article  PubMed  Google Scholar 

  51. Li D, Ropert N, Koulakoff A, Giaume C, Oheim M (2008) Lysosomes are the major vesicular compartment undergoing Ca2+-regulated exocytosis from cortical astrocytes. J Neurosci 28(30):7648–7658. https://doi.org/10.1523/JNEUROSCI.0744-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Limmroth V, Putzki N, Kachuck NJ (2011) The interferon beta therapies for treatment of relapsing-remitting multiple sclerosis: are they equally efficacious? A comparative review of open-label studies evaluating the efficacy, safety, or dosing of different interferon beta formulations alone or in combination. Ther Adv Neurol Disord 4(5):281–296. https://doi.org/10.1177/1756285611413825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Makhlouf K, Weiner HL, Khoury SJ (2002) Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol). CNS Drugs 16(1):1–8

    Article  CAS  PubMed  Google Scholar 

  54. Mantegazza AR, Magalhaes JG, Amigorena S, Marks MS (2013) Presentation of phagocytosed antigens by MHC class I and II. Traffic 14(2):135–152. https://doi.org/10.1111/tra.12026

    Article  CAS  PubMed  Google Scholar 

  55. Mattson MP, Camandola S (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107(3):247–254. https://doi.org/10.1172/JCI11916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8(9):913–919. https://doi.org/10.1038/ni1507

    Article  CAS  PubMed  Google Scholar 

  57. Meno-Tetang GM, Li H, Mis S, Pyszczynski N, Heining P, Lowe P, Jusko WJ (2006) Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab Dispos 34(9):1480–1487. https://doi.org/10.1124/dmd.105.009001

    Article  CAS  PubMed  Google Scholar 

  58. Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J (2015) Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum Mol Genet 24(17):4958–4970. https://doi.org/10.1093/hmg/ddv218

    Article  CAS  PubMed  Google Scholar 

  59. Miron VE, Schubart A, Antel JP (2008) Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 274(1–2):13–17. https://doi.org/10.1016/j.jns.2008.06.031

    Article  CAS  PubMed  Google Scholar 

  60. Nikcevich KM, Gordon KB, Tan L, Hurst SD, Kroepfl JF, Gardinier M, Barrett TA, Miller SD (1997) IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J Immunol 158(2):614–621

    CAS  PubMed  Google Scholar 

  61. Noursadeghi M, Tsang J, Haustein T, Miller RF, Chain BM, Katz DR (2008) Quantitative imaging assay for NF-kappaB nuclear translocation in primary human macrophages. J Immunol Methods 329(1–2):194–200. https://doi.org/10.1016/j.jim.2007.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S (2003) The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 554(1–2):189–193

    Article  CAS  PubMed  Google Scholar 

  63. Payne SG, Oskeritzian CA, Griffiths R, Subramanian P, Barbour SE, Chalfant CE, Milstien S, Spiegel S (2007) The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 109(3):1077–1085. https://doi.org/10.1182/blood-2006-03-011437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10(3):253–263. https://doi.org/10.1016/S1474-4422(11)70015-1

    Article  CAS  PubMed  Google Scholar 

  65. Potokar M, Kreft M, Pangrsic T, Zorec R (2005) Vesicle mobility studied in cultured astrocytes. Biochem Biophys Res Commun 329(2):678–683. https://doi.org/10.1016/j.bbrc.2005.02.030

    Article  CAS  PubMed  Google Scholar 

  66. Potokar M, Stenovec M, Kreft M, Gabrijel M, Zorec R (2011) Physiopathologic dynamics of vesicle traffic in astrocytes. Histol Histopathol 26(2):277–284

    PubMed  Google Scholar 

  67. Ransohoff RM, Estes ML (1991) Astrocyte expression of major histocompatibility complex gene products in multiple sclerosis brain tissue obtained by stereotactic biopsy. Arch Neurol 48(12):1244–1246

    Article  CAS  PubMed  Google Scholar 

  68. Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A et al (2017) Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A 114(8):2012–2017. https://doi.org/10.1073/pnas.1615413114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ruijter JM, Ramakers C, Hoogaars WM, Karlen Y, Bakker O, van den Hoff MJ, Moorman AF (2009) Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res 37(6):e45. https://doi.org/10.1093/nar/gkp045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sato K, Malchinkhuu E, Horiuchi Y, Mogi C, Tomura H, Tosaka M, Yoshimoto Y, Kuwabara A et al (2007) Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes. J Neurochem 103(6):2610–2619. https://doi.org/10.1111/j.1471-4159.2007.04958.x

    Article  CAS  PubMed  Google Scholar 

  71. Satoh J, Paty DW, Kim SU (1995) Differential effects of beta and gamma interferons on expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 in cultured fetal human astrocytes. Neurology 45(2):367–373

    Article  CAS  PubMed  Google Scholar 

  72. Schwartz JP, Wilson DJ (1992) Preparation and characterization of type 1 astrocytes cultured from adult rat cortex, cerebellum, and striatum. Glia 5(1):75–80. https://doi.org/10.1002/glia.440050111

    Article  CAS  PubMed  Google Scholar 

  73. Sehrawat S, Rouse BT (2008) Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators. J Immunol 180(11):7636–7647

    Article  CAS  PubMed  Google Scholar 

  74. Soos JM, Morrow J, Ashley TA, Szente BE, Bikoff EK, Zamvil SS (1998) Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation to encephalitogenic T cells. J Immunol 161(11):5959–5966

    CAS  PubMed  Google Scholar 

  75. Stenovec M, Kreft M, Poberaj I, Betz WJ, Zorec R (2004) Slow spontaneous secretion from single large dense-core vesicles monitored in neuroendocrine cells. FASEB J 18(11):1270–1272. https://doi.org/10.1096/fj.03-1397fje

    Article  CAS  PubMed  Google Scholar 

  76. Stenovec M, Milosevic M, Petrusic V, Potokar M, Stevic Z, Prebil M, Kreft M, Trkov S et al (2011) Amyotrophic lateral sclerosis immunoglobulins G enhance the mobility of Lysotracker-labelled vesicles in cultured rat astrocytes. Acta Physiol (Oxford) 203(4):457–471. https://doi.org/10.1111/j.1748-1716.2011.02337.x

    Article  CAS  Google Scholar 

  77. Stenovec M, Trkov S, Kreft M, Zorec R (2014) Alterations of calcium homoeostasis in cultured rat astrocytes evoked by bioactive sphingolipids. Acta Physiol (Oxford) 212(1):49–61. https://doi.org/10.1111/apha.12314

    Article  CAS  Google Scholar 

  78. Stenovec M, Trkov S, Lasič E, Terzieva S, Kreft M, Rodríguez Arellano JJ, Parpura V, Verkhratsky A et al (2016) Expression of familial Alzheimer disease presenilin 1 gene attenuates vesicle traffic and reduces peptide secretion in cultured astrocytes devoid of pathologic tissue environment. Glia 64(2):317–329. https://doi.org/10.1002/glia.22931

    Article  PubMed  Google Scholar 

  79. Takabe K, Kim RH, Allegood JC, Mitra P, Ramachandran S, Nagahashi M, Harikumar KB, Hait NC et al (2010) Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2. J Biol Chem 285(14):10477–10486. https://doi.org/10.1074/jbc.M109.064162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tan L, Gordon KB, Mueller JP, Matis LA, Miller SD (1998) Presentation of proteolipid protein epitopes and B7-1-dependent activation of encephalitogenic T cells by IFN-gamma-activated SJL/J astrocytes. J Immunol 160(9):4271–4279

    CAS  PubMed  Google Scholar 

  81. Tholanikunnel BG, Granneman JG, Malbon CC (1995) The M(r) 35,000 beta-adrenergic receptor mRNA-binding protein binds transcripts of G-protein-linked receptors which undergo agonist-induced destabilization. J Biol Chem 270(21):12787–12793

    Article  CAS  PubMed  Google Scholar 

  82. Tian GF, Azmi H, Takano T, Xu Q, Peng W, Lin J, Oberheim N, Lou N et al (2005) An astrocytic basis of epilepsy. Nat Med 11(9):973–981. https://doi.org/10.1038/nm1277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Traugott U, Scheinberg LC, Raine CS (1985) On the presence of Ia-positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation. J Neuroimmunol 8(1):1–14

    Article  CAS  PubMed  Google Scholar 

  84. Trkov S, Stenovec M, Kreft M, Potokar M, Parpura V, Davletov B, Zorec R (2012) Fingolimod—a sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes. Glia 60(9):1406–1416. https://doi.org/10.1002/glia.22361

    Article  PubMed  PubMed Central  Google Scholar 

  85. Tuomi JM, Voorbraak F, Jones DL, Ruijter JM (2010) Bias in the Cq value observed with hydrolysis probe based quantitative PCR can be corrected with the estimated PCR efficiency value. Methods 50(4):313–322. https://doi.org/10.1016/j.ymeth.2010.02.003

    Article  CAS  PubMed  Google Scholar 

  86. van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van het Hof B, Kooij G, Reijerkerk A et al (2012) Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathol 124(3):397–410. https://doi.org/10.1007/s00401-012-1014-4

    Article  CAS  PubMed  Google Scholar 

  87. Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD et al (2010) Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia 58(12):1465–1476. https://doi.org/10.1002/glia.21021

    Article  PubMed  Google Scholar 

  88. van Loo G, De Lorenzi R, Schmidt H, Huth M, Mildner A, Schmidt-Supprian M, Lassmann H, Prinz MR et al (2006) Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol 7(9):954–961. https://doi.org/10.1038/ni1372

    Article  CAS  PubMed  Google Scholar 

  89. Vardjan N, Gabrijel M, Potokar M, Svajger U, Kreft M, Jeras M, de Pablo Y, Faiz M et al (2012) IFN-γ-induced increase in the mobility of MHC class II compartments in astrocytes depends on intermediate filaments. J Neuroinflammation 9:144. https://doi.org/10.1186/1742-2094-9-144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vardjan N, Kreft M, Zorec R (2014) Dynamics of β-adrenergic/cAMP signaling and morphological changes in cultured astrocytes. Glia 62(4):566–579. https://doi.org/10.1002/glia.22626

    Article  PubMed  Google Scholar 

  91. Vardjan N, Parpura V, Zorec R (2016) Loose excitation-secretion coupling in astrocytes. Glia 64(5):655–667. https://doi.org/10.1002/glia.22920

    Article  PubMed  Google Scholar 

  92. Vascotto F, Lankar D, Faure-André G, Vargas P, Diaz J, Le Roux D, Yuseff MI, Sibarita JB et al (2007) The actin-based motor protein myosin II regulates MHC class II trafficking and BCR-driven antigen presentation. J Cell Biol 176(7):1007–1019. https://doi.org/10.1083/jcb.200611147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Verkhratsky A, Matteoli M, Parpura V, Mothet JP, Zorec R (2016) Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. EMBO J 35(3):239–257. https://doi.org/10.15252/embj.201592705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98(1):239–389. https://doi.org/10.1152/physrev.00042.2016

    Article  CAS  PubMed  Google Scholar 

  95. Wiegmann K, Muthyala S, Kim DH, Arnason BG, Chelmicka-Schorr E (1995) Beta-adrenergic agonists suppress chronic/relapsing experimental allergic encephalomyelitis (CREAE) in Lewis rats. J Neuroimmunol 56(2):201–206

    Article  CAS  PubMed  Google Scholar 

  96. Wu C, Leong SY, Moore CS, Cui QL, Gris P, Bernier LP, Johnson TA, Séguéla P et al (2013) Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J Neuroinflammation 10:41. https://doi.org/10.1186/1742-2094-10-41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zeinstra E, Wilczak N, Chesik D, Glazenburg L, Kroese FG, De Keyser J (2006) Simvastatin inhibits interferon-gamma-induced MHC class II up-regulation in cultured astrocytes. J Neuroinflammation 3(16):16. https://doi.org/10.1186/1742-2094-3-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zeinstra E, Wilczak N, De Keyser J (2000) [3H] dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain. Neurosci Lett 289(1):75–77

    Article  CAS  PubMed  Google Scholar 

  99. Zeinstra E, Wilczak N, De Keyser J (2003) Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2. J Neuroimmunol 135(1–2):166–171

    Article  CAS  PubMed  Google Scholar 

  100. Zeinstra E, Wilczak N, Streefland C, De Keyser J (2000) Astrocytes in chronic active multiple sclerosis plaques express MHC class II molecules. Neuroreport 11(1):89–91

    Article  CAS  PubMed  Google Scholar 

  101. Zhang Y, Li X, Ciric B, Ma CG, Gran B, Rostami A, Zhang GX (2017) Effect of fingolimod on neural stem cells: a novel mechanism and broadened application for neural repair. Mol Ther 25(2):401–415. https://doi.org/10.1016/j.ymthe.2016.12.008

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The authors acknowledge the financial support from the Slovenian Research Agency (research core funding P3-310 and P3-0043) and projects J3 6790, J3 6789, and J3 7605, CipKeBip, COST Action BM1002, EU COST Action CM1207—GLISTEN, and EU COST Action CM1207—EuroCellNet.

Author information

Authors and Affiliations

  1. Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000, Ljubljana, Slovenia

    Saša Trkov Bobnar, Matjaž Stenovec & Robert Zorec

  2. Celica Biomedical, Tehnološki park 24, 1000, Ljubljana, Slovenia

    Saša Trkov Bobnar, Matjaž Stenovec & Robert Zorec

  3. Laboratory for Molecular Neurobiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000, Ljubljana, Slovenia

    Katarina Miš & Sergej Pirkmajer

Authors
  1. Saša Trkov Bobnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matjaž Stenovec
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katarina Miš
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sergej Pirkmajer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Zorec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Zorec.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. Care of the experimental animals was in accordance with European and Slovenian legislation (Official Gazette of the RS 38/13; UVHVVR, no. U34401-47/2014/7). This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trkov Bobnar, S., Stenovec, M., Miš, K. et al. Fingolimod Suppresses the Proinflammatory Status of Interferon-γ-Activated Cultured Rat Astrocytes. Mol Neurobiol 56, 5971–5986 (2019). https://doi.org/10.1007/s12035-019-1481-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1481-x

Keywords

Search

Navigation