Sphingosine kinase 2 in autoimmune/inflammatory disease and development of sphingosine kinase 2 inhibitors

Nigel J. Pyne; David R. Adams; Susan Pyne

doi:10.1016/j.tips.2017.04.003

Sphingosine kinase 2 in autoimmune/inflammatory disease and development of sphingosine kinase 2 inhibitors

Nigel J. Pyne, David R. Adams, Susan Pyne

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Literature review › peer-review

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Abstract

The purpose of this Opinion is to present a case for targeting sphingosine
kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using
Sphk2^-/- mice suggest that SK2 is an anti-inflammatory enzyme, although
this might be misleading because of a compensatory increase in the expression
of a second isoform, sphingosine kinase 1 (SK1), which functions as a
proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.

Original language	English
Pages (from-to)	581-591
Number of pages	10
Journal	Trends in Pharmacological Sciences
Volume	38
Issue number	7
Early online date	9 Jun 2017
DOIs	https://doi.org/10.1016/j.tips.2017.04.003
Publication status	Published - 31 Jul 2017

Keywords

sphingosine kinase
autoimmune disease
interleukin
interferon-γ
histone deacetylase
retinoid-related orphan receptor-γt

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Pyne-etal-TPS2017-Sphingosine-kinase-2-in-autoimmune-inflammatory-diseaseAccepted author manuscript, 1.03 MBLicence: CC BY-NC-ND 4.0

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@article{659eec17a34c451b9bc8401c7f0d0b54,

title = "Sphingosine kinase 2 in autoimmune/inflammatory disease and development of sphingosine kinase 2 inhibitors",

abstract = "The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2-/- mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.",

keywords = "sphingosine kinase, autoimmune disease, interleukin, interferon-γ, histone deacetylase, retinoid-related orphan receptor-γt",

author = "Pyne, \{Nigel J.\} and Adams, \{David R.\} and Susan Pyne",

year = "2017",

month = jul,

day = "31",

doi = "10.1016/j.tips.2017.04.003",

language = "English",

volume = "38",

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journal = "Trends in Pharmacological Sciences",

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TY - JOUR

T1 - Sphingosine kinase 2 in autoimmune/inflammatory disease and development of sphingosine kinase 2 inhibitors

AU - Pyne, Nigel J.

AU - Adams, David R.

AU - Pyne, Susan

PY - 2017/7/31

Y1 - 2017/7/31

N2 - The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2-/- mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.

AB - The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2-/- mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.

KW - sphingosine kinase

KW - autoimmune disease

KW - interleukin

KW - interferon-γ

KW - histone deacetylase

KW - retinoid-related orphan receptor-γt

UR - http://www.sciencedirect.com/science/journal/01656147?sdc=1

U2 - 10.1016/j.tips.2017.04.003

DO - 10.1016/j.tips.2017.04.003

M3 - Literature review

SN - 0165-6147

VL - 38

SP - 581

EP - 591

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 7

ER -

Sphingosine kinase 2 in autoimmune/inflammatory disease and development of sphingosine kinase 2 inhibitors

Abstract

Keywords

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