抑制鞘氨醇激酶 1 的新功能可抑制 JNK 活性，从而预防炎症和损伤。
A novel function of sphingosine kinase 1 suppression of JNK activity in preventing inflammation and injury.
机构信息
Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois 60612, USA.
出版信息
J Biol Chem. 2010 May 21;285(21):15848-57. doi: 10.1074/jbc.M109.075549. Epub 2010 Mar 18.
Abstract
The mechanism underlying the protective effect of sphingosine kinase 1 (SphK1) in inflammatory injury is not clear. We demonstrated using SphK1-null mice (SphK1(-/-)) the crucial role of SphK1 in suppressing lipopolysaccharide-induced neutrophil oxidant production and sequestration in lungs and mitigating lung inflammatory injury. This effect of SphK1 was independent of the production of sphingosine 1-phosphate, the product of SphK1 activity. The anti-inflammatory effect of SphK1 in the lipopolysaccharide model was mediated through SphK1 interaction with JNK. SphK1 stabilization of JNK in turn inhibited JNK binding to the JNK-interacting protein 3 (JIP3) and thus abrogated the activation of NADPH oxidase and oxidant generation and resultant NF-kappaB activation. Therefore, SphK1-mediated down-regulation of JNK activity serves to dampen inflammation and tissue injury.
摘要
丝氨酸激酶 1（SphK1）在炎症损伤中具有保护作用的机制尚不清楚。我们利用 SphK1 基因敲除小鼠（SphK1（-/-））证明了 SphK1 在抑制脂多糖诱导的中性粒细胞氧化产物产生和在肺部蓄积以及减轻肺炎症损伤方面的关键作用。SphK1 的这种作用不依赖于 SphK1 活性产物 1-磷酸鞘氨醇的产生。SphK1 在脂多糖模型中的抗炎作用是通过 SphK1 与 JNK 的相互作用介导的。SphK1 稳定 JNK 进而抑制 JNK 与 JNK 相互作用蛋白 3（JIP3）的结合，从而阻断 NADPH 氧化酶的激活、氧化产物的产生以及 NF-κB 的激活。因此，SphK1 介导的 JNK 活性下调有助于抑制炎症和组织损伤。
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