European Center for Brain Research (CERC)/Santa Lucia Foundation, Rome, Italy.
PLoS One. 2010 Jan 14;5(1):e8688. doi: 10.1371/journal.pone.0008688.
Anandamide (AEA) is an endogenous lipid mediator that exerts several effects in the brain as well as in peripheral tissues. These effects are mediated mainly by two types of cannabinoid receptors, named CB(1)R and CB(2)R, making AEA a prominent member of the "endocannabinoid" family. Also immune cells express CB(1) and CB(2) receptors, and possess the whole machinery responsible for endocannabinoid metabolism. Not surprisingly, evidence has been accumulated showing manifold roles of endocannabinoids in the modulation of the immune system. However, details of such a modulation have not yet been disclosed in primary human T-cells.
METHODOLOGY/SIGNIFICANCE: In this investigation we used flow cytometry and ELISA tests, in order to show that AEA suppresses proliferation and release of cytokines like IL-2, TNF-alpha and INF-gamma from activated human peripheral T-lymphocytes. However, AEA did not exert any cytotoxic effect on T-cells. The immunosuppression induced by AEA was mainly dependent on CB(2)R, since it could be mimicked by the CB(2)R selective agonist JWH-015, and could be blocked by the specific CB(2)R antagonist SR144528. Instead the selective CB(1)R agonist ACEA, or the selective CB(1)R antagonist SR141716, were ineffective. Furthermore, we demonstrated an unprecedented immunosuppressive effect of AEA on IL-17 production, a typical cytokine that is released from the unique CD4+ T-cell subset T-helper 17.
CONCLUSIONS/SIGNIFICANCE: Overall, our study investigates for the first time the effects of the endocannabinoid AEA on primary human T-lymphocytes, demonstrating that it is a powerful modulator of immune cell functions. In particular, not only we clarify that CB(2)R mediates the immunosuppressive activity of AEA, but we are the first to describe such an immunosuppressive effect on the newly identified Th-17 cells. These findings might be of crucial importance for the rational design of new endocannabinoid-based immunotherapeutic approaches.
花生四烯酸乙醇胺（AEA）是一种内源性脂质介质，在大脑和外周组织中发挥多种作用。这些作用主要由两种类型的大麻素受体介导，分别称为 CB(1)R 和 CB(2)R，使 AEA 成为“内源性大麻素”家族的重要成员。同样，免疫细胞表达 CB(1)和 CB(2)受体，并具有负责内源性大麻素代谢的全套机制。毫不奇怪，已经积累了证据表明内源性大麻素在免疫系统调节中具有多种作用。然而，在原代人 T 细胞中，这种调节的细节尚未揭示。
方法/意义：在这项研究中，我们使用流式细胞术和 ELISA 检测，表明 AEA 抑制了激活的人外周 T 淋巴细胞的增殖和细胞因子如白细胞介素-2（IL-2）、肿瘤坏死因子-α（TNF-α）和干扰素-γ（INF-γ）的释放。然而，AEA 对 T 细胞没有任何细胞毒性作用。AEA 诱导的免疫抑制主要依赖于 CB(2)R，因为它可以被 CB(2)R 选择性激动剂 JWH-015 模拟，并可以被 CB(2)R 特异性拮抗剂 SR144528 阻断。相反，选择性 CB(1)R 激动剂 ACEA 或选择性 CB(1)R 拮抗剂 SR141716 无效。此外，我们还证明了 AEA 对白细胞介素-17（IL-17）产生的前所未有的免疫抑制作用，IL-17 是一种独特的 CD4+T 细胞亚群辅助性 T 细胞 17（T-helper 17）释放的典型细胞因子。
结论/意义：总的来说，我们的研究首次调查了内源性大麻素 AEA 对原代人 T 淋巴细胞的影响，证明它是免疫细胞功能的强大调节剂。特别是，我们不仅阐明了 CB(2)R 介导了 AEA 的免疫抑制活性，而且我们是第一个描述这种对新发现的 Th-17 细胞的免疫抑制作用的人。这些发现对于基于内源性大麻素的新免疫治疗方法的合理设计可能具有至关重要的意义。
