Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase.
Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase.
复制标题
DOI：
10.1038/s41467-018-06158-5
复制
发表时间：
2018-09-20
影响因子：
16.6
通讯作者：
Koeberle A
中科院分区：
文献类型：
--
作者：
Pein H;Ville A;Pace S;Temml V;Garscha U;Raasch M;Alsabil K;Viault G;Dinh CP;Guilet D;Troisi F;Neukirch K;König S;Bilancia R;Waltenberger B;Stuppner H;Wallert M;Lorkowski S;Weinigel C;Rummler S;Birringer M;Roviezzo F;Sautebin L;Helesbeux JJ;Séraphin D;Mosig AS;Schuster D;Rossi A;Richomme P;Werz O;Koeberle A
系统性维生素E代谢物被认为是信号分子，但其生理作用尚不清楚。在这里，我们表明，通过库筛选潜在的人类维生素E代谢物，长链ω-羧酸是有效的变构抑制剂5-脂氧合酶，在化学引诱剂和血管活性白三烯的生物合成中的关键酶。13-（（2 R）-6-羟基-2，5，7，8-四甲基苯并二氢吡喃-2-基）-2，6，10-三甲基十三烷酸（α-T-13′-COOH）可在人肝芯片中由α-生育酚合成，并在抑制人白细胞中5-脂氧合酶的浓度（8-49 nM）下在人和小鼠血浆中检出。α-T-13′-COOH在免疫细胞和发炎的小鼠渗出液中蓄积，在体外和体内选择性抑制5-脂氧合酶衍生的脂质介质的生物合成，并有效抑制腹膜炎和哮喘小鼠模型中的炎症和支气管高反应性。总之，我们的数据表明，α-生育酚的免疫调节和抗炎功能取决于其内源性代谢产物α-T-13′-COOH，可能通过抑制免疫细胞中的5-脂氧合酶。维生素E代谢物被认为具有信号传导能力，但它们如何调节免疫反应仍不清楚。在此，作者表明维生素E代谢物α-T-13′-COOH可抑制5-脂氧合酶，从而抑制免疫激活和炎症反应的脂质介质的合成。
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells. Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.
登录
查看更多内容
影响因子：
16.6
作者：
Dvash E;Har-Tal M;Barak S;Meir O;Rubinstein M
通讯作者：
Rubinstein M
影响因子：
15.9
作者：
JAFFE, EA;NACHMAN, RL;MINICK, CR
通讯作者：
MINICK, CR
影响因子：
6.5
作者：
Jiang, Qing;Freiser, Helene;Yin, Xinmin
通讯作者：
Yin, Xinmin
影响因子：
16.6
作者：
Fredman, Gabrielle;Hellmann, Jason;Proto, Jonathan D.;Kuriakose, George;Colas, Romain A.;Dorweiler, Bernhard;Connolly, E. Sander;Solomon, Robert;Jones, David M.;Heyer, Eric J.;Spite, Matthew;Tabas, Ira
通讯作者：
Tabas, Ira
影响因子：
13.5
作者：
Cerec, Virginie;Glaise, Denise;Corlu, Anne
通讯作者：
Corlu, Anne