MAST-CELLS EXPRESS A PERIPHERAL CANNABINOID RECEPTOR WITH DIFFERENTIAL SENSITIVITY TO ANANDAMIDE AND PALMITOYLETHANOLAMIDE
MAST-CELLS EXPRESS A PERIPHERAL CANNABINOID RECEPTOR WITH DIFFERENTIAL SENSITIVITY TO ANANDAMIDE AND PALMITOYLETHANOLAMIDE
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DOI：
10.1073/pnas.92.8.3376
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发表时间：
1995-04-11
影响因子：
11.1
通讯作者：
LEON, A
中科院分区：
文献类型：
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作者：
FACCI, L;DALTOSO, R;LEON, A
肥大细胞是在粘膜和结缔组织以及神经系统中发现的多功能骨髓源性细胞，它们在组织炎症和神经免疫相互作用中发挥重要作用。关于能够调节肥大细胞活化的内源性分子和机制知之甚少。在外周组织中发现的棕榈酰乙醇胺被认为是一种能够下调肥大细胞活化和炎症的局部自分泌物。花生四烯酸的乙醇酰胺是一种同源的N-酰胺，存在于大脑中，是中枢大麻素受体（CB 1）的候选内源性激动剂。由于在外周组织中发现了第二种大麻素受体（CB 2），因此研究了肥大细胞上可能存在的CB 2受体及其与N-酰胺的相互作用。在这里，我们报告，肥大细胞表达的基因和功能的CB 2受体蛋白与肥大细胞活化的负调控作用。尽管棕榈酰乙醇酰胺和花生四烯酸酰胺都与CB 2受体结合，但只有前者在体外下调肥大细胞活化。此外，棕榈酰乙醇酰胺的功能效应以及活性大麻素的功能效应被大麻素有效地拮抗。结果表明：（i）外周类Cannahinoid CB 2受体在激动剂结合后控制肥大细胞活化，从而控制炎症;（ii）棕榈酰乙醇胺，与大麻素不同，作为肥大细胞上CB 2受体的内源性激动剂;（iii）天然存在的分子对肥大细胞的调节活性加强了所提出的自体素局部炎症拮抗（阿利亚）机制;和（iv）棕榈酰乙醇酰胺及其衍生物可以提供特异性靶向肥大细胞的抗肿瘤治疗策略（“ALIA酰胺”）。
Mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play important roles in tissue inflammation and in neuroimmune interactions. Very little is known about endogenous molecules and mechanisms capable of modulating mast cell activation. Palmitoylethanolamide, found in peripheral tissues, has been proposed to behave as a local autacoid capable of downregulating mast cell activation and inflammation. A cognate N-acylamide, anandamide, the ethanolamide of arachidonic acid, occurs in brain and is a candidate endogenous agonist for the central cannabinoid receptor (CB1). As a second cannabinoid receptor (CB2) has been found in peripheral tissues, the possible presence of CB2 receptors on mast cells and their interaction with N-acylamides was investigated. Here we report that mast cells express both the gene and a functional CB2 receptor protein with negative regulatory effects on mast cell activation. Although both palmitoylethanolalmide and anandamide bind to the CB2 receptor, only the former downmodulates mast cell activation in vitro. Further, the functional effect of palmitoylethanolamide, as well as that of the active cannabinoids, was efficiently antagonized by anandamide. The results suggest that (i) peripheral cannahinoid CB2 receptors control, upon agonist binding, mast cell activation and therefore inflammation; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for the CB2 receptor on mast cells; (iii) modulatory activities on mast cells exerted by the naturally occurring molecule strengthen a proposed autacoid local inflammation antagonism (ALIA) mechanism; and (iv) palmitoylethanolamide and its derivatives may provide antiinflammatory therapeutic strategies specifically targeted to mast cells (''ALIAmides'').