Ebenezer David L, Fu Panfeng, Suryadevara Vidyani, Zhao Yutong, Natarajan Viswanathan
Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
Adv Biol Regul. 2017 Jan;63:156-166. doi: 10.1016/j.jbior.2016.09.007. Epub 2016 Sep 29.
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. .
1-磷酸鞘氨醇（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催化的合成以及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通过G蛋白偶联的S1P1 - 5受体进行的独特的由内而外（细胞外）信号传导以及细胞内受体非依赖性信号传导。此外，由核SphK2在细胞核中产生的S1P调节HDAC1/2活性，调节组蛋白乙酰化以及促炎基因的转录。在此，我们展示了关于S1P裂解酶介导的S1P信号传导在调节肺内皮细胞中脂多糖（LPS）诱导的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裂解酶对S1P的降解产生Δ2 - 十六碳烯醛和磷酸乙醇胺，并且在内皮细胞胞质区室中产生的长链脂肪醛似乎调节组蛋白乙酰化模式，这与核SphK2/S1P信号传导以及HDAC1/2的抑制不同。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。通过诸如根皮素等细胞可渗透剂或其他醛捕获剂分别捕获源自S1P降解和脂质过氧化的脂肪醛和其他短链醛（如4 - 羟基壬烯醛），可能有助于通过调节组蛋白乙酰化来治疗脓毒症诱导的肺部炎症。
