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.
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