Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK.
Trends Pharmacol Sci. 2017 Jul;38(7):581-591. doi: 10.1016/j.tips.2017.04.003. Epub 2017 Jun 9.
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.
本观点旨在提出针对自身免疫/炎症性疾病中的鞘氨醇激酶 2 (SK2) 的靶点。使用 Sphk2 小鼠获得的数据表明，SK2 是一种抗炎酶，尽管这可能会产生误导，因为第二种同工酶——鞘氨醇激酶 1 (SK1) 的表达代偿性增加，而 SK1 则作为促炎酶发挥作用。SK2 参与调节白细胞介素 (IL)-12/干扰素 γ (IFN-γ) 和组蛋白去乙酰化酶-1/2 (HDAC-1/2) 信号，并且可能与辅助性 T 细胞 (Th)17 细胞极化相关的维甲酸相关孤儿受体 γ t (ROR-γt) 的稳定性有关。因此，需要开发对 SK1 具有高选择性的高度有效的 SK2 抑制剂，以明确 SK2 在自身免疫/炎症性疾病中的作用。相对于 SK1 的 SK2 的结构决定因素将能够设计选择性 SK2 抑制剂。
