Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent process
Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent process
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DOI：
10.1016/j.bbalip.2020.158611
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发表时间：
2020-04-01
影响因子：
4.8
通讯作者：
Wheelock, Craig E.
中科院分区：
文献类型：
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作者：
Fuchs, David;Tang, Xiao;Wheelock, Craig E.
三羟基十八烯酸(TriHOME)是亚油酸衍生的脂质介质，据报道在阻塞性肺疾病中调节失调。与许多其他氧脂不同的是，人类对TriHOME的生物合成仍然知之甚少。TriHOME与炎症的关系促使目前对人粒细胞合成16种不同的9，10，13-TriHOME和9，12，13-TriHOME异构体的能力以及TriHOME生物合成途径的研究。在与亚油酸孵育后，嗜酸性粒细胞和肥大细胞系LAD2(程度较小)形成了TriHOME，但没有中性粒细胞。立体化学分析表明，嗜酸性粒细胞产生的TriHOME主要为13(S)构型，提示15-脂氧合酶(15-LOX)介导的合成。与15-LOX抑制剂BLX-3887孵育后，TriHOME的形成被阻断，并被证明在很大程度上不依赖于可溶性环氧化物水解酶和细胞色素P450的活性。当亚油酸被13-HODE取代时，三HOME的合成被取消，但在与13-HpODE的孵育中，三HOME的合成增加，这表明环氧醇在三HOME的形成中起中介作用。与嗜酸性粒细胞不同，LAD2细胞形成了以13(R)构型为主的TriHOME，这表明形成TriHOME有多种合成途径。这些发现首次深入了解了TriHOME在人类中的合成途径，并扩大了我们对它们在炎症性疾病中形成的理解。
Trihydroxyoctadecenoic acids (TriHOMEs) are linoleic acid-derived lipid mediators reported to be dysregulated in obstructive lung disease. In contrast to many other oxylipins, TriHOME biosynthesis in humans is still poorly understood. The association of TriHOMEs with inflammation prompted the current investigation into the ability of human granulocytes to synthesize the 16 different 9,10,13-TriHOME and 9,12,13-TriHOME isomers and of the TriHOME biosynthetic pathway. Following incubation with linoleic acid, eosinophils and (to a lesser extent) the mast cell line LAD2, but not neutrophils, formed TriHOMEs. Stereochemical analysis revealed that TriHOMEs produced by eosinophils predominantly evidenced the 13(S) configuration, suggesting 15-lipoxygenase (15-LOX)-mediated synthesis. TriHOME formation was blocked following incubation with the 15-LOX inhibitor BLX-3887 and was shown to be largely independent of soluble epoxide hydrolase and cytochrome P450 activities. TriHOME synthesis was abolished when linoleic acid was replaced with 13-HODE, but increased in incubations with 13-HpODE, indicating the intermediary role of epoxy alcohols in TriHOME formation. In contrast to eosinophils, LAD2 cells formed TriHOMEs having predominantly the 13(R) configuration, demonstrating that there are multiple synthetic routes for TriHOME formation. These findings provide for the first-time insight into the synthetic route of TriHOMEs in humans and expand our understanding of their formation in inflammatory diseases.