MODULATION OF T CELL ACTIVITY BY 2-ARACHIDONYL GLYCEROL

描述：(申请人提供)： 这个实验室之前的研究已经证明了显著的 一种内源性物质对IL-2的浓度依赖性抑制作用 大麻素，2-花生四烯基甘油(2-AG)，在激活的T细胞中，但它还 尚不清楚这种抑制是否通过大麻素受体介导， CB1和/或CB2。CB2受体特别令人感兴趣，因为它具有 比CB1受体表达水平高得多。我们的大多数人 到目前为止，观察到的是小鼠T细胞。我们现在感兴趣的是 2-AG对人T细胞系Jurkat E6-1和Jurkat E6-1的作用 HPB-ALL，分别表达异常和正常的CB2受体。这个 Jurkat和HPB-ALL细胞系与CB2拮抗剂SR144528、 将使我们能够确定人类T细胞中2-AG的活性是否通过 通过CB2受体。初步研究结果如下 观察：2-AG对IL2的抑制不能被CB1/CB2逆转 B)2-AG抑制HPB-ALL细胞IL-2转录，但不抑制HPB-ALL细胞IL-2转录 Jurkat细胞，它表达异常的CB2受体；以及c)矛盾的是， 2-AG还能促进T细胞的增殖。这些观察结果导致了 假设：2-花生四烯基甘油促进CB1/CB2中T细胞的增殖 细胞周期调控和/或ERK图改变的独立机制 激酶，同时抑制IL-2的产生。这一假设将通过以下方式进行检验 三个特定目标(SA)：SA1)表征2-AG对 IL-2在人T细胞中的转录和分泌；SA2)在 2-AG对人T细胞增殖的影响 2-氨基半乳糖对细胞周期蛋白依赖性激酶作用的研究 抑制物p16、p21和p27，以及丝裂原激活的激酶ERK1和ERK1 ERK2.

DESCRIPTION: (Provided by Applicant): Previous studies in this laboratory have demonstrated a marked and concentration-dependent inhibition of IL-2 by a putative endogenous cannabinoid, 2-arachidonyl glycerol (2-AG), in activated T cells, but it is yet unknown whether this inhibition is mediated through the cannabinoid receptors, CB1 and/or CB2. The CB2 receptor is of particular interest because it has a much higher level of expression than the CB1 receptor. The majority of our observations have thus far been in murine T cells. We are now interested in characterizing the effect of 2-AG in two human T cell lines, Jurkat E6-1 and HPB-ALL, which express an aberrant and normal CB2 receptor, respectively. The Jurkat and HPB-ALL cell lines in conjunction with the CB2 antagonist, SR144528, will allow us to determine if the activity of 2-AG in human T cells is mediated through the CB2 receptor. Preliminary studies led to the following observations: a) the inhibition of IL2 by 2-AG was not reversed by CB1/CB2 antagonists; b) 2-AG inhibited IL-2 transcription in HPB-ALL cells, but not in Jurkat cells, which express an aberrant CB2 receptor; and c) paradoxically, 2-AG also enhances T cell proliferation. These observations led to the hypothesis: 2-arachidonyl glycerol enhances T cell proliferation in a CB1/CB2 independent mechanism through alterations in cell cycle control and/or ERK MAP kinases, while inhibiting IL-2 production. This hypothesis will be tested using three specific aims (SA): SA1) characterization of the effects of 2-AG upon IL-2 transcription and secretion in human T cells; SA2) characterization on the effects of 2-AG upon T cell proliferation in human T cells; and SA3) characterization of the effects of 2-AG on the cyclin dependent kinase inhibitors, p16, p21, and p27, and the mitogen-activated kinases, ERK1 and ERK2.