Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase.
Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase.
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DOI：
10.1016/j.jbior.2016.09.007
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发表时间：
2017-01
影响因子：
--
通讯作者：
Natarajan V
中科院分区：
文献类型：
--
作者：
Ebenezer DL;Fu P;Suryadevara V;Zhao Y;Natarajan V
鞘氨醇-1-磷酸（S1P）是最简单的生物活性鞘脂，其细胞水平受到鞘氨醇激酶（SphKs） 1和2的合成和S1P磷酸酶、脂质磷酸磷酸酶和S1P裂解酶介导的降解的严格调控。S1P的多效性作用归因于其独特的通过g蛋白偶联S1P1-5受体和细胞内受体独立信号传导的由内到外（细胞外）信号传导。此外，核SphK2在细胞核中产生的S1P调节HDAC1/2活性，调节组蛋白乙酰化和促炎基因的转录。在这里，我们提供了关于S1P裂解酶介导的S1P信号在调节lps诱导的肺内皮炎症中的作用的数据。阻断S1P裂解酶的表达或活性可减弱lps诱导的组蛋白乙酰化和促炎细胞因子的分泌。S1P裂解酶降解S1P产生Δ2-hexadecenal和磷酸乙醇胺，内皮细胞胞质室中产生的长链脂肪醛似乎调节组蛋白乙酰化模式，这与细胞核SphK2/S1P信号传导和抑制HDAC1/2不同。这些体外研究表明，S1P衍生的长链脂肪醛可能是脓毒症诱导的肺部炎症中促炎基因的表观遗传调节剂。通过细胞渗透剂如根皮素或其他醛捕获剂分别捕获脂肪醛和其他短链醛，如由S1P降解和脂质过氧化产生的4-羟基壬烯醛，可能有助于通过调节组蛋白乙酰化治疗败血症诱导的肺部炎症。
Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation.