Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors

Trends Pharmacol Sci. 2017 Jul;38(7):581-591. doi: 10.1016/j.tips.2017.04.003. Epub 2017 Jun 9.

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

Publication types

  • Review

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / enzymology*
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / enzymology*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • Protein Kinase Inhibitors
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase