Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid.
Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid.
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DOI：
10.1074/jbc.m112.340612
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发表时间：
2012-03-23
期刊：
影响因子：
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通讯作者：
Arai H
中科院分区：
文献类型：
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作者：
Isobe Y;Arita M;Matsueda S;Iwamoto R;Fujihara T;Nakanishi H;Taguchi R;Masuda K;Sasaki K;Urabe D;Inoue M;Arai H
背景：控制异常炎症的内源性介质作为新疗法的潜在靶点而受到关注。结果：在这里，我们鉴定了一种新的omega-3脂肪酸衍生的抗炎介质17，18-diHEPE，表示为resolvin E3。结论：Resolvin E3在体内外均具有抑制中性粒细胞趋化的作用。意义：本研究的意义在于鉴定了一种具有强效抗炎特性的新型内源性脂质介质。源自ω-3二十碳五烯酸（EPA）的生物活性介质引起有效的抗炎作用。在这里，我们鉴定了新的EPA代谢物，包括来自18-HEPE的8，18-二羟基二十碳五烯酸（8，18-diHEPE）、11，18-diHEPE、12，18-diHEPE和17，18-diHEPE。与消退素E1和E2不同，两者都是由中性粒细胞通过5-脂氧合酶途径生物合成的，这些代谢产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-diHEPE的两种立体异构体，统称为消退素E3（RvE 3），通过限制酵母多糖诱导的腹膜炎中的中性粒细胞浸润而显示出有效的抗炎作用。通过高分辨率NMR明确确定RvE 3的平面结构为17，18-二羟基-5Z，8 Z，11 Z，13 E，15 E-EPE，并且使用化学合成的18 R-和18 S-HEPE作为前体，将两种立体异构体分别指定为具有17，18 R-和17，18 S-二羟基。在低纳摩尔浓度下，18 R-和18 S-RvE 3均抑制体外中性粒细胞趋化性。这些发现表明，RvE 3有助于EPA在控制炎症和相关疾病方面的有益作用。
Background: Endogenous mediators that control aberrant inflammation are of interest as potential targets of new therapeutics. Results: Here, we identified a novel omega-3 fatty acid-derived anti-inflammatory mediator 17,18-diHEPE, denoted as resolvin E3. Conclusion: Resolvin E3 has a potent inhibitory action on neutrophil chemotaxis both in vitro and in vivo. Significance: The significance of this study is the identification of a novel endogenous lipid mediator with a potent anti-inflammatory property. 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.