Departments of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; Business-Academia-Collaborative Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Departments of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, Japan.
J Biol Chem. 2012 Mar 23;287(13):10525-10534. doi: 10.1074/jbc.M112.340612. Epub 2012 Jan 24.
Bioactive mediators derived from omega-3 eicosapentaenoic acid (EPA) elicit potent anti-inflammatory actions. Here, we identified novel EPA metabolites, including 8,18-dihydroxyeicosapentaenoic acid (8,18-diHEPE), 11,18-diHEPE, 12,18-diHEPE, and 17,18-diHEPE from 18-HEPE. Unlike resolvins E1 and E2, both of which are biosynthesized by neutrophils via the 5-lipoxygenase pathway, these metabolites are biosynthesized by eosinophils via the 12/15-lipoxygenase pathway. Among them, two stereoisomers of 17,18-diHEPE, collectively termed resolvin E3 (RvE3), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in zymosan-induced peritonitis. The planar structure of RvE3 was unambiguously determined to be 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-EPE by high resolution NMR, and the two stereoisomers were assigned to have 17,18R- and 17,18S-dihydroxy groups, respectively, using chemically synthesized 18R- and 18S-HEPE as precursors. Both 18R- and 18S-RvE3 inhibited neutrophil chemotaxis in vitro at low nanomolar concentrations. These findings suggest that RvE3 contributes to the beneficial actions of EPA in controlling inflammation and related diseases.
源自 ω-3 二十碳五烯酸 (EPA) 的生物活性介质引发强烈的抗炎作用。在这里，我们从 18-HEPE 中鉴定出新型 EPA 代谢物，包括 8,18-二羟二十碳五烯酸 (8,18-diHEPE)、11,18-二羟二十碳五烯酸、12,18-二羟二十碳五烯酸和 17,18-二羟二十碳五烯酸。与均由中性粒细胞通过 5-脂氧合酶途径生物合成的 resolvin E1 和 E2 不同，这些代谢物是由嗜酸性粒细胞通过 12/15-脂氧合酶途径生物合成的。其中，17,18-二羟二十碳五烯酸的两种立体异构体，统称为 resolvin E3 (RvE3)，通过限制酵母聚糖诱导的腹膜炎中性粒细胞浸润，显示出强烈的抗炎作用。RvE3 的平面结构通过高分辨率 NMR 明确确定为 17,18-二羟基-5Z,8Z,11Z,13E,15E-EPE，并且使用化学合成的 18R-和 18S-HEPE 作为前体，分别将两种立体异构体分配为具有 17,18R-和 17,18S-二羟基。18R-和 18S-RvE3 均在体外以低纳摩尔浓度抑制中性粒细胞趋化性。这些发现表明 RvE3 有助于 EPA 控制炎症和相关疾病的有益作用。
