Facci L, Dal Toso R, Romanello S, Buriani A, Skaper S D, Leon A
Researchlife, Castelfranco Veneto (TV), Italy.
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-80. doi: 10.1073/pnas.92.8.3376.
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 palmitoylethanolamide 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 cannabinoid 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").
肥大细胞是源自骨髓的多功能细胞，存在于黏膜、结缔组织和神经系统中，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，人们了解甚少。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反应的局部自分泌调节因子。一种相关的N-酰基酰胺——花生四烯酸乙醇胺（即阿南达胺）存在于大脑中，是中枢大麻素受体（CB1）的内源性激动剂候选物。由于在外周组织中发现了第二种大麻素受体（CB2），因此研究了肥大细胞上CB2受体的可能存在情况及其与N-酰基酰胺的相互作用。在此我们报告，肥大细胞表达CB2受体基因及功能性蛋白，对肥大细胞活化具有负调节作用。虽然棕榈酰乙醇胺和阿南达胺都能与CB2受体结合，但只有前者能在体外下调肥大细胞活化。此外，阿南达胺能有效拮抗棕榈酰乙醇胺以及活性大麻素的功能作用。结果表明：（i）外周大麻素CB2受体在激动剂结合后可控制肥大细胞活化，进而控制炎症反应；（ii）与阿南达胺不同，棕榈酰乙醇胺是肥大细胞上CB2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强化了一种假定的自分泌调节因子局部炎症拮抗（ALIA）机制；（iv）棕榈酰乙醇胺及其衍生物可能提供专门针对肥大细胞的抗炎治疗策略（“ALIAmides”）。
