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.

该意见的目的是介绍针对自身免疫性/炎性疾病中的鞘氨醇激酶2（SK2）的病例。使用Sphk2获得的数据^-/-小鼠认为，SK2是一种抗炎酶，尽管这可能会引起误解，因为第二种亚型鞘氨醇激酶1（SK1）的表达具有补偿性增加，而后者又起着促炎酶的作用。SK2参与调节白介素（IL）-12 /干扰素γ（IFN-γ）和组蛋白脱乙酰基酶-1/2（HDAC-1 / 2）信号传导，并可能参与类视黄醇相关的孤儿受体γt（ROR-γt）稳定性与T辅助（Th）17细胞极化有关。因此，需要开发对SK1具有选择性的高效SK2抑制剂，以清楚地确定SK2在自身免疫/炎性疾病中的作用。相对于SK1的SK2结构决定因素将使选择性SK2抑制剂的设计成为可能。