Cannabinoid Modulation of Macrophage Function

描述（由申请人提供）：大麻是美国使用最广泛的非法药物。δ-9-四氢大麻酚（THC）是大麻中的主要精神活性成分，据报道具有免疫抑制作用，并改变巨噬细胞的功能活动。THC和各种大麻素抑制巨噬细胞迁移和吞噬作用，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，并将细胞因子的全身平衡从Th 1促炎性改变为Th 2抗炎性。既然内源性大麻素（endocannabinoid）系统已被确定为具有两种受体类型，几种信号转导途径，三种突出的endocannabinoid，以及用于endocannabinoid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）会改变这种内源性系统。因此，大麻素对巨噬细胞功能的影响的定义是重要的，因为大麻被用作治疗慢性致残性疾病，包括艾滋病的药物。本研究的目的是确定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，但这种相互作用的后果是独特的。也就是说，与外源性大麻素相反，内源性大麻素的作用可能是局部的，持续时间短。这种区别可能阐明了外源性大麻素抑制内源性大麻素系统作用的一种模式。为了验证这些假设，三个具体目标将作为研究的指导方针。首先，建议定义内源性大麻素对巨噬细胞在定义的激活状态下的签名功能活动的影响。将评估花生四烯酸乙醇酰胺（anandamide）、2-花生四烯酸甘油（2-AG）和noladin醚的作用。第二，建议将内源性大麻素的体外作用与THC的作用进行比较。第三，建议通过一系列选择性实验来确定体外效应在体内是否有效。

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.