Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation
Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation
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DOI：
10.4049/jimmunol.178.6.3912
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
--
作者：
Arita, Makoto;Ohira, Taisuke;Serhan, Charles N.
解决素E1(RvE1)是一种有效的抗炎和促炎介质，源于炎症消退阶段产生的omega-3二十碳五烯酸。RvE1具有独特的结构和反向调节作用，可以在多种炎症模型中阻止人多形核白细胞(PMN)的内皮迁移和PMN的渗透。为了研究中性粒细胞抗炎作用的机制(S)，我们制备了[H-3]RvE1，并研究了它与人PMN的相互作用。与人PMN膜部分结合的结果显示与人PMN的K-d为48.3 nM。[H-3]白三烯B-4和白三烯受体1拮抗剂U-75302可取代Rve1与人中性粒细胞的特异性结合，但不能被另一种Rve1受体ChemR23的特异性配基趋化素肽取代。重组人BLT1与[H-3]RvE1特异性结合，K-d为45 nM。RvE1对BLT1有选择性抑制腺苷环化酶的作用，但对BLT2无抑制作用。在人外周血单核细胞中，Rvel可部分诱导钙动员，并阻断LTB4随后的刺激作用。Rvel还可减弱LTB4诱导的BLT1细胞中的核因子-kappaB的激活。在体内，在BLT1基因敲除小鼠中，RVELL的抗炎作用在低剂量(100 Ng)静脉注射时显著降低。腹膜炎。相反，在较高剂量下(1.0微克静脉注射)以BLT1非依赖的方式显著减少PMN的渗透。这些结果表明，RVIL以部分激动剂的形式与BLT1结合，与其他受体(例如，ChemR23介导的逆调节作用)一起，潜在地作为白细胞上BLT1信号的局部阻尼器，介导炎症的消退。
Resolvin E1 (RvE1) is a potent anti-inflammatory and proresolving mediator derived from omega-3 eicosapentaenoic acid generated during the resolution phase of inflammation. RvE1 possesses a unique structure and counterregulatory actions that stop human polymorphonuclear leukocyte (PMN) transendothelial migration and PMN infiltration in several murine inflammatory models. To examine the mechanism(s) underlying anti-inflammatory actions on PMNs, we prepared [H-3]RvE1 and characterized its interactions with human PMN. Results with membrane fractions of human PMN demonstrated specific binding with a K-d of 48.3 nM. [H-3]RvE1 specific binding to human PMN was displaced by leukotriene B-4 (LTB4) and LTB4 receptor 1 (BLT1) antagonist U-75302, but not by chemerin peptide, a ligand specific for another RvE1 receptor ChemR23. Recombinant human BLT1 gave specific binding with [H-3]RvE1 with a K-d of 45 nM. RvE1 selectively inhibited adenylate cyclase with BLT1, but not with BLT2. In human PBMC, RvEl partially induced calcium mobilization, and blocked subsequent stimulation by LTB4. RvEl also attenuated LTB4 induced NF-kappa B activation in BLT1-transfected cells. In vivo anti-inflammatory actions of RvEl were sharply reduced in BLT1 knockout mice when given at low doses (100 ng i.v.) in peritonitis. In contrast, RvEl at higher doses (1.0 mu g i.v.) significantly reduced PMN infiltration in a BLT1-independent manner. These results indicate that RvEl binds to BLT1 as a partial agonist, potentially serving as a local damper of BLT1 signals on leukocytes along with other receptors (e.g., ChemR23-mediated counterregulatory actions) to mediate the resolution of inflammation.