Cannabinoid Modulation of Macrophage Function

描述(申请人提供)：大麻是美国使用最广泛的非法药物。据报道，大麻中的主要精神活性成分Delta-9-四氢大麻酚(THC)具有免疫抑制作用，并能改变巨噬细胞的功能活动。THC和各种大麻素抑制巨噬细胞的迁移和吞噬，抑制趋化因子的产生，改变抗原的加工，下调促炎细胞因子的产生，并改变全身细胞因子的平衡，从Th1促炎到Th2抗炎。既然内源性大麻素系统已经被确定有两种受体类型，几条信号转导途径，三种重要的内源性大麻素，以及内源性大麻素的合成、细胞摄取和代谢的特定途径，我们的前提是外源性大麻素如THC改变这一内源系统。因此，鉴于利用大麻作为治疗包括艾滋病在内的慢性致残性疾病的药物的倡议，界定大麻对巨噬细胞功能的影响是重要的。本研究的目的是明确内源性和外源性大麻素在巨噬细胞功能调节中的作用。有待检验的中心假设是，内源性大麻素通过大麻素受体发挥作用。然而，我们进一步提出，虽然内源性大麻素和外源性大麻素通过这些受体起作用，但这种相互作用的结果是不同的。也就是说，与外源性大麻素相比，内源性大麻素的影响可能是局部的，持续时间较短。这一区别可能阐明了外源性大麻素对内源性大麻素系统的叠加作用模式。为了检验这些假设，三个具体目标将作为研究的指导方针。首先，有人建议定义内源性大麻素在巨噬细胞处于确定的激活状态时对其特征功能活动的影响。将评估花生四烯基乙醇胺、2-花生四烯基甘油(2-AG)和诺拉丁醚的效果。其次，建议比较内源性大麻素和THC的体外作用。第三，建议通过一系列精选实验来确定体外效应是否在体内起作用。

DESCRIPTION (provided by applicant): Marijuana is the most widely used illicit drug in the United States. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, has been reported to be immunosuppressive and to alter the functional activities of macrophages. THC and various cannabinoids inhibit macrophage migration and phagocytosis, dampen production of chemokines, alter processing of antigens, down-regulate production of pro-inflammatory cytokines, and alter the systemic balance of cytokines from a Th1 pro-inflammatory to a Th2 anti-inflammatory profile. Now that an endogenous cannabinoid (endocannabinoid) system has been identified as having two receptor types, several signal transduction pathways, three prominent endocannabinoids, and specific pathways for the synthesis, cellular uptake and metabolism of the endocannabinoids, it is our premise that exogenous cannabinoids such as THC alter this endogenous system. Thus, definition of the effects of cannabinoids on macrophage function is important in view of initiatives to use marijuana as a medicinal for treatment of chronic disabling diseases, including AIDS. The objective of this study is to define the role of endogenous and exogenous cannabinoids in the modulation of macrophage function. The central hypothesis to be tested is that endocannabinoids exert their actions through cannabinoid receptors. However, we propose further that while endocannabinoids and exogenous cannabinoids act through these receptors, the consequences of such interactions are distinctive. That is, in contrast to exogenous cannabinoids, the effects of endocannabinoids may be localized and of short duration. This distinction may articulate a mode by which exogenous cannabinoids superimpose effects over the endocannabinoid system. In order to test these hypotheses, three Specific Aims will serve as guidelines to the research. First, it is proposed to define the effects of endocannabinoids on signature functional activities attributed to macrophages when in defined states of activation. The effects of arachidonylethanolamide (anandamide), 2-arachidonylglycerol (2-AG), and noladin ether will be assessed. Second, it is proposed to compare the in vitro effects endocannabinoids to those of THC. Third, it is proposed through a series of select experiments to determine whether in vitro effects are operative in vivo.