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

Mark Barbour, Melissa McNaughton, Stephanie D. Boomkamp, Neil MacRitchie, Hui-Rong Jiang, Nigel J Pyne, Susan Pyne

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.
LanguageEnglish
Pages210-222
Number of pages13
JournalBritish Journal of Pharmacology
Volume174
Issue number2
Early online date20 Dec 2016
DOIs
Publication statusPublished - 1 Jan 2017

Fingerprint

Lysosphingolipid Receptors
Autoimmune Experimental Encephalomyelitis
Interleukin-1beta
Inflammation
Sphingosine
Disease Progression
Spinal Cord
Macrophages
Methyl Ethers
Lymphopenia
Azides
Multiple Sclerosis
Anti-Inflammatory Agents
T-Lymphocytes
sphingosine kinase
Fingolimod Hydrochloride
In Vitro Techniques
sphingosine 1-phosphate

Keywords

  • Sphingosine kinase
  • sphingosine 1-phosphate
  • inflammasome
  • multiple sclerosis
  • experimental autoimmune encephalomyelitis
  • autoimmune inflammatory demyelinating disease
  • T-lymphocytes
  • pathogen-associated molecular patterns

Cite this

@article{0bc97acfa1e947e0b6ed4f307bea04c8,
title = "Effect of sphingosine kinase modulators on interleukin-1β release, sphingosine 1-phosphate receptor 1 expression and experimental autoimmune encephalomyelitis: FTY720 analogues and inflammation",
abstract = "Background and Purpose: The sphingosine analogue, FTY720 (Gilenya{\circledR}) 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.",
keywords = "Sphingosine kinase, sphingosine 1-phosphate, inflammasome, multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune inflammatory demyelinating disease, T-lymphocytes, pathogen-associated molecular patterns",
author = "Mark Barbour and Melissa McNaughton and Boomkamp, {Stephanie D.} and Neil MacRitchie and Hui-Rong Jiang and Pyne, {Nigel J} and Susan Pyne",
note = "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.",
year = "2017",
month = "1",
day = "1",
doi = "10.1111/bph.13670",
language = "English",
volume = "174",
pages = "210--222",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
number = "2",

}

TY - JOUR

T1 - Effect of sphingosine kinase modulators on interleukin-1β release, sphingosine 1-phosphate receptor 1 expression and experimental autoimmune encephalomyelitis

T2 - British Journal of Pharmacology

AU - Barbour, Mark

AU - McNaughton, Melissa

AU - Boomkamp, Stephanie D.

AU - MacRitchie, Neil

AU - Jiang, Hui-Rong

AU - Pyne, Nigel J

AU - Pyne, Susan

N1 - 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.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Sphingosine kinase

KW - sphingosine 1-phosphate

KW - inflammasome

KW - multiple sclerosis

KW - experimental autoimmune encephalomyelitis

KW - autoimmune inflammatory demyelinating disease

KW - T-lymphocytes

KW - pathogen-associated molecular patterns

UR - http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381

U2 - 10.1111/bph.13670

DO - 10.1111/bph.13670

M3 - Article

VL - 174

SP - 210

EP - 222

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 2

ER -