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

Pyne, Nigel J. and Adams, David R. and Pyne, Susan (2017) Sphingosine kinase 2 in autoimmune/inflammatory disease and development of sphingosine kinase 2 inhibitors. Trends in Pharmacological Sciences, 38 (7). pp. 581-591. ISSN 0165-6147 (https://doi.org/10.1016/j.tips.2017.04.003)

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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.

ORCID iDs

Pyne, Nigel J. ORCID logoORCID: https://orcid.org/0000-0002-5657-4578, Adams, David R. and Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584;
CORE (COnnecting REpositories)