Levy B D, Petasis N A, Serhan C N
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 1997 Oct 30;389(6654):985-90. doi: 10.1038/40180.
In response to environmental stimuli, leukocyte membrane remodelling generates biologically active lipids that can serve as both intra- and extracellular mediators. There are several classes of lipids that can mediate inflammatory reactions. We report here on a new intracellular lipid signal that regulates oxygen-radical formation in neutrophils, a key response in microbial killing, inflammation and tissue injury. Screening of neutrophil-derived extracts rich in phosphorylated, non-saponifiable lipids revealed a potent inhibitor of superoxide anion (O2-) production. Structural analysis of biologically active fractions gave four major phosphorylated lipids: most abundant was presqualene diphosphate (PSDP). Upon activation of neutrophil receptors, PSDP and its monophosphate form, presqualene monophosphate (PSMP), undergo rapid remodelling. At submicromolar concentrations, PSDP but not PSMP inhibit O2- production by human neutrophil cell-free oxidase preparations. We prepared PSDP and PSMP by total organic synthesis and matched both the physical properties and biological activity of the neutrophil-derived compounds. Our results indicate that PSDP, a recognized intermediate of cholesterol biosynthesis, is present in immune effector cells and is a potent regulator of the cellular response in host defence.
作为对环境刺激的反应，白细胞膜重塑会产生具有生物活性的脂质，这些脂质既可以作为细胞内介质，也可以作为细胞外介质。有几类脂质可以介导炎症反应。我们在此报告一种新的细胞内脂质信号，它调节中性粒细胞中的氧自由基形成，这是微生物杀伤、炎症和组织损伤中的关键反应。对富含磷酸化、不可皂化脂质的中性粒细胞提取物进行筛选，发现了一种超氧阴离子（O2-）产生的强效抑制剂。对生物活性组分的结构分析得到了四种主要的磷酸化脂质：最丰富的是前鲨烯二磷酸（PSDP）。当中性粒细胞受体激活时，PSDP及其单磷酸形式前鲨烯单磷酸（PSMP）会迅速重塑。在亚微摩尔浓度下，PSDP而非PSMP可抑制人中性粒细胞无细胞氧化酶制剂产生O2-。我们通过全有机合成制备了PSDP和PSMP，并使其与中性粒细胞衍生化合物的物理性质和生物活性相匹配。我们的结果表明，PSDP是胆固醇生物合成的一种公认中间体，存在于免疫效应细胞中，并且是宿主防御中细胞反应的强效调节剂。
