The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis
The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis
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DOI：
10.4049/jimmunol.1002853
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发表时间：
2011-03-01
影响因子：
4.4
通讯作者：
Flamand, Nicolas
中科院分区：
文献类型：
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作者：
Chouinard, Francois;Lefebvre, Julie S.;Flamand, Nicolas
虽然内源性大麻素是伤害感受和肥胖的重要参与者，但它们作为免疫调节剂的作用仍然难以捉摸。迄今为止描述的主要内源性大麻素，即2-花生四烯酸-甘油（2-AG）和花生四烯酸-乙醇酰胺（AEA），诱导一个有趣的概况的促炎和抗炎作用。这可能与细胞特异性大麻素受体表达和/或内源性大麻素衍生代谢物的作用有关。重要的是，2-AG和AEA在其结构中包含花生四烯酸（AA）分子，并且快速水解。我们假设如下：1）内源性大麻素水解释放的AA将代谢成类二十烷酸;和2）这些类二十烷酸将介导内源性大麻素的一些作用。为了证实这些假设，进行了实验，其中新鲜分离的人中性粒细胞用内源性大麻素处理。与AEA不同，2-AG刺激中性粒细胞释放髓过氧化物酶，激活激酶和钙动员。虽然2-AG不诱导中性粒细胞的迁移，但它诱导中性粒细胞迁移活性的释放。2-AG也迅速（1分钟）诱导了一个强大的生物合成的白三烯，类似于AA观察到的。大麻素受体激动剂或拮抗剂分别不能模拟或阻止2-AG的作用。最后，阻断2-AG水解、白三烯（LT）B-4生物合成或LTB 4受体1激活可阻止2-AG对中性粒细胞功能的所有影响。总之，我们证明了2-AG有效地激活人中性粒细胞。这是2-AG水解、LTB 4从头生物合成和涉及LTB 4受体1的自分泌激活环的结果。免疫学杂志，2011，186：3188-3196。
Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro-and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B-4 biosynthesis, or LTB4 receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB4 biosynthesis, and an autocrine activation loop involving LTB4 receptor 1. The Journal of Immunology, 2011, 186: 3188-3196.