Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation
Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation
复制标题
DOI：
10.1172/jci42545
复制
发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
--
作者：
Oh, Sungwhan F.;Pillai, Padmini S.;Serhan, Charles N.
E系列溶血素是来源于omega-3多不饱和脂肪酸二十碳五烯酸(EPA)的抗炎和促溶脂介质，它能有效清除炎症，促进组织动态平衡。阿司匹林除了发挥抗血栓作用外，还会触发这些特殊的促分解介质的生物合成。在这里，我们使用代谢组学方法研究了人体血清中具有特定手性化学的E系列解析素的生物合成，并为新的18S系列解析素提供了证据。与已知的解析素前体18R-HEPE相比，阿司匹林增加了18S-羟基二十碳五烯酸酯(18S-HEPE)的内源形成。人重组5-脂氧合酶以这两种对映体为底物，重组LTA(4)水解酶(LTA4H)将含5S(6)-环氧化物的手性中间体转化为拆分蛋白EL和18S-拆分蛋白EL(分别为RvE1和18S-RvE1)。18S-RvE1与白细胞GPCRs ChemR23和BLT1结合的亲和力和效力比R-差向异构体更强，但脱氢酶使18S-RvE1失活更快。在小鼠腹膜炎模型中，18S-RvE1能增强巨噬细胞对酵母菌、大肠杆菌和中性粒细胞的吞噬作用，减少中性粒细胞的侵袭和炎性细胞因子的产生。这些结果表明，在E系列解旋素的生物合成中，有两条平行的立体特异性途径，18R-和18S-，它们是抗炎、促拆分和非炎性的，可能有助于阿司匹林和omega-3多不饱和脂肪酸的有益作用。
E-series resolvins are antiinflammatory and pro-resolving lipid mediators derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) that actively clear inflammation to promote tissue homeostasis. Aspirin, in addition to exerting antithrombotic actions, also triggers the biosynthesis of these specialized pro-resolving mediators. Here, we used metabolomic profiling to investigate the biosynthesis of E-series resolvins with specific chiral chemistry in serum from human subjects and present evidence for new 18S series resolvins. Aspirin increased endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a known resolvin precursor. Human recombinant 5-lipoxygenase used both enantiomers as substrates, and recombinant LTA(4) hydrolase (LTA4H) converted chiral 5S(6)-epoxide-containing intermediates to resolvin El and 18S-resolvin El (RvE1 and 18S-RvE1, respectively). 18S-RvE1 bound to the leukocyte GPCRs ChemR23 and BLT1 with increased affinity and potency compared with the R-epimer, but was more rapidly inactivated than RvE1 by dehydrogenase. Like RvE1, 18S-RvE1 enhanced macrophage phagocytosis of zymosan, E. coli, and apoptotic neutrophils and reduced both neutrophil infiltration and proinflammatory cytokines in murine peritonitis. These results demonstrate two parallel stereospecific pathways in the biosynthesis of E-series resolvins, 18R- and 18S-, which are antiinflammatory, pro-resolving, and non-phlogistic and may contribute to the beneficial actions of aspirin and omega-3 polyunsaturated fatty acids.