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Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors
Trends in Pharmacological Sciences ( IF 13.9 ) Pub Date : 2017-06-09 , DOI: 10.1016/j.tips.2017.04.003
Nigel J. Pyne , David R. Adams , Susan Pyne

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.



中文翻译:

鞘氨醇激酶2在自身免疫性/炎性疾病中和鞘氨醇激酶2抑制剂的发展

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。

更新日期:2017-06-09
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