A Novel Function of Sphingosine Kinase 1 Suppression of JNK Activity in Preventing Inflammation and Injury
A Novel Function of Sphingosine Kinase 1 Suppression of JNK Activity in Preventing Inflammation and Injury
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DOI：
10.1074/jbc.m109.075549
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发表时间：
2010-05-21
影响因子：
4.8
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
--
作者：
Di, Anke;Kawamura, Takeshi;Malik, Asrar B.
鞘氨酸激酶1 （SphK1）在炎症损伤中的保护作用机制尚不清楚。我们用SphK1缺失小鼠（SphK1(-/-)）证明了SphK1在抑制脂多糖诱导的肺中性粒细胞氧化产生和封存以及减轻肺炎症损伤中的关键作用。SphK1的这种作用与SphK1活性的产物-磷酸鞘氨醇的产生无关。SphK1在脂多糖模型中的抗炎作用是通过SphK1与JNK相互作用介导的。SphK1稳定JNK反过来抑制JNK与JNK相互作用蛋白3 （JIP3）的结合，从而消除NADPH氧化酶的激活和氧化剂的产生以及由此产生的NF-kappa B的激活。因此，sphk1介导的JNK活性下调有助于减轻炎症和组织损伤。
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-kappa B activation. Therefore, SphK1-mediated down-regulation of JNK activity serves to dampen inflammation and tissue injury.