Effect of sphingosine kinase modulators on interleukin-1β release, sphingosine 1-phosphate receptor 1 expression and experimental autoimmune encephalomyelitis : FTY720 analogues and inflammation

Barbour, Mark and McNaughton, Melissa and Boomkamp, Stephanie D. and MacRitchie, Neil and Jiang, Hui-Rong and Pyne, Nigel J and Pyne, Susan (2017) Effect of sphingosine kinase modulators on interleukin-1β release, sphingosine 1-phosphate receptor 1 expression and experimental autoimmune encephalomyelitis : FTY720 analogues and inflammation. British Journal of Pharmacology, 174 (2). pp. 210-222. ISSN 1476-5381

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    Abstract

    Background and Purpose: The sphingosine analogue, FTY720 (Gilenya®) alleviates clinical disease progression in multiple sclerosis. Here we variously assessed the effects of an azide analogue of (S)-FTY720 vinylphosphonate (compound 5; a sphingosine kinase 1 activator), (R)-FTY720 methyl ether (ROMe, a sphingosine kinase 2 inhibitor) and RB-020 (a sphingosine kinase 1 inhibitor and sphingosine kinase 2 substrate) on IL-1beta formation, sphingosine 1-phosphate levels and S1P1 expression. We also assessed the effect of compound 5 and ROMe in an experimental autoimmune encephalomyelitis (EAE) model. Experimental Approach: We measured IL-1beta formation by macrophages, sphingosine 1-phosphate levels and S1P1 expression levels in vitro and clinical score and inflammatory cell infiltration into the spinal cord in vivo. Key Results: Treatment of differentiated U937 macrophages with compound 5, RB-020 or sphingosine (but not ROMe) enhanced IL-1beta release. This data suggests these compounds might be pro-inflammatory in vitro. However, compound 5 or ROMe reduced disease progression and infiltration of inflammatory cells into the spinal cord in EAE and ROMe induced a reduction in CD4+ and CD8+ T-cell levels in the blood (lymphopenia). Indeed, ROMe induced a marked decrease in cell surface S1P1 expression in vitro. Conclusion and Implications: This is the first demonstration that an activator of SK1 (compound 5) and an inhibitor of SK2 (ROMe, which also reduces cell surface S1P1 expression) have an anti-inflammatory action in EAE.

    Author(s):Barbour, Mark ORCID logoORCID: https://orcid.org/0000-0003-1547-1289, McNaughton, Melissa ORCID logoORCID: https://orcid.org/0000-0001-5080-6043, Boomkamp, Stephanie D., MacRitchie, Neil, Jiang, Hui-Rong, Pyne, Nigel J ORCID logoORCID: https://orcid.org/0000-0002-5657-4578 and Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584
    Item type:Article
    ID code:58650
    Notes:This is the peer reviewed version of the following article: Barbour, M., McNaughton, M., Boomkamp, S. D., MacRitchie, N., Jiang, H-R., Pyne, N., & Pyne, S. (2016). Effect of sphingosine kinase modulators on interleukin-1β release, sphingosine 1-phosphate receptor 1 expression and experimental autoimmune encephalomyelitis: FTY720 analogues and inflammation. British Journal of Pharmacology, which has been published in final form at https://doi.org/10.1111/bph.13670. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
    Keywords:Sphingosine kinase, sphingosine 1-phosphate, inflammasome, multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune inflammatory demyelinating disease, T-lymphocytes, pathogen-associated molecular patterns, Immunology, Internal medicine, Immunology, Immunology and Allergy
    Subjects:Science > Microbiology > Immunology
    Medicine > Internal medicine
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:15 Nov 2016 11:29
    Last modified:17 Jan 2020 23:00
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/58650
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