Effect of the Psychoactive Metabolite of Marijuana, Δ9-Tetrahydrocannabinol (THC), on the Synthesis of Tumor Necrosis Factor by Human Large Granular Lymphocytes

Kusher, David I.; Dawson, Laura O.; Taylor, Ann; Djeu, Julie Y.

doi:10.1006/cimm.1994.1060

Cited by 36 publications

(17 citation statements)

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“…8X). DISCUSSION ⌬ 9 -THC, the active constituent of marijuana, is known to suppress a variety of immune cell functions in vitro and in vivo (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), although the mechanism of action is not yet fully elucidated. Several lines of evidence strongly suggest that at least a part of this cannabinoid-induced immune suppression is mediated through specific receptor sites for cannabinoids expressed on immune cells.…”

Section: -Arachidonoylglycerol and The Cb2 Receptormentioning

confidence: 99%

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Evidence That 2-Arachidonoylglycerol but Not N-Palmitoylethanolamine or Anandamide Is the Physiological Ligand for the Cannabinoid CB2 Receptor

Sugiura

Kondo

Kishimoto

et al. 2000

Journal of Biological Chemistry

360

270

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We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca 2؉ concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca 2؉ concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca 2؉ transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. G i or G o is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system. ⌬ 9 -Tetrahydrocannabinol (⌬ 9 -THC), 1 a major psychoactive constituent of marijuana, is known to exert a variety of pharmacological effects on laboratory animals and humans. When administered orally or intravenously, ⌬ 9 -THC induces reduced spontaneous motor activity, analgesia, heightened sensory awareness, euphoria, and impairment of short-term memory (1). ⌬ 9 -THC is also known to exert profound effects on several biological systems other than the central nervous system; for example, ⌬ 9 -THC exhibits potent immunosuppressive activities (2-12). The mechanism underlying such diverse actions of ⌬ 9 -THC remained obscure until the late 1980s. -THC itself bind to a specific receptor site(s) thereby eliciting a variety of responses. To date, two types of cannabinoid receptors have been identified as follows: the CB1 receptor expressed primarily in the nervous system (14), and the CB2 receptor expressed mainly in the immune system (15). Both are seven transmembrane, G protein-coupled receptors, and they share 44% overall identity (68% identity for transmembrane domains) (15).The discovery of specific receptors for cannabinoids prompted the search for endogenous ligands. To date, two types of arachidonic acid-containing molecules, anandamide (16) and 2-arachidonoylglycerol (2-AG) (17, 18), have been reported as putative endogenous cannabinoid receptor ligands. Anandamide was isolated from porcine brain (16), and 2-AG was isolated from rat brain (17) and canine gut...

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Section: -Arachidonoylglycerol and The Cb2 Receptormentioning

confidence: 99%

“…⌬ 9 -THC is also known to exert profound effects on several biological systems other than the central nervous system; for example, ⌬ 9 -THC exhibits potent immunosuppressive activities (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The mechanism underlying such diverse actions of ⌬ 9 -THC remained obscure until the late 1980s.…”

mentioning

confidence: 99%

Evidence That 2-Arachidonoylglycerol but Not N-Palmitoylethanolamine or Anandamide Is the Physiological Ligand for the Cannabinoid CB2 Receptor

Sugiura

Kondo

Kishimoto

et al. 2000

Journal of Biological Chemistry

360

270

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“…Most of the in vitro studies showed immunosuppressive effects of cannabinoids (CB): inhibition of mitogeninduced proliferative responses of T-lymphocytes and B-lymphocytes [2,3], of cytotoxic T-cell activity [4], of macrophage microbiocidal activity and TNFcz synthesis [5,6], of cytolytic activity and TNFc~ production of large granular lymphocytes [7]. In some studies, enhancing effects were observed: increase of interleukin-1 bioactivity by mouse resident macrophages or human differentiated macrophagic cell lines due to increased levels of TNF~z [8,9].…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids enhance human B‐cell growth at low nanomolar concentrations

et al. 1995

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This study examined the effect of cannabinoid ligands on human tonsillar B-cells activated either through cross-linking of surface immunoglobulins or ligation of the CD40 antigen. The two synthetic cannabinoids, CP55,940 and WIN55212-2, as well as Ag-tetrahydrocannabinol (THC), the psychoactive component of marijuana, caused a dose-dependent increase of B-cell proliferation and displayed ECso at low nanomolar concentrations. This cannabinoid-induced enhancing activity was inhibited by pertussis toxin which suggested a G-protein-coupled receptor process. In addition, the absence of antagonistic effect of SR141716A, a specific CB1 receptor antagonist, together with the demonstration that human B-cells displayed large amount of CB2 receptor mRNAs, led us to assume that the growth enhancing activity observed on B-cells at very low concentrations of cannabinoids could be mediated through the CB2 receptor.

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“…In addition to its effects on the CNS, THC is an immune modulator, with in vitro and in vivo studies indicating immunosuppressive effects on macrophages (2)(3)(4)(5), NK cells (6,7), and T lymphocytes (8 -11). The recent documentation of specific cannabinoid receptor expression by leukocytes has generated increased interest in the immunomodulatory effects of THC (7,12).…”

mentioning

confidence: 99%

Δ-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway

Zhu

Sharma

Stolina³

et al. 2000

The Journal of Immunology

235

160

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In this study, we show that Δ-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, suppresses host immune reactivity against lung cancer. In two different weakly immunogenic murine lung cancer models, intermittent administration of THC (5 mg/kg, four times/wk i.p. for 4 wk) led to accelerated growth of tumor implants compared with treatment with diluent alone. In contrast to our findings in immunocompetent mice, THC did not affect tumor growth in tumor-bearing SCID mice. The immune inhibitory cytokines, IL-10 and TGF-β, were augmented, while IFN-γ was down-regulated at both the tumor site and in the spleens of THC-treated mice. Administration of either anti-IL-10- or anti-TGF-β-neutralizing Abs prevented the THC-induced enhancement in tumor growth. Both APC and T cells from THC-treated mice showed limited capacities to generate alloreactivity. Furthermore, lymphocytes from THC-treated mice transferred the effect to normal mice, resulting in accelerated tumor growth similar to that seen in the THC-treated mice. THC decreased tumor immunogenicity, as indicated by the limited capacity for tumor-immunized, THC-treated mice to withstand tumor rechallenge. In vivo administration of a specific antagonist of the CB2 cannabinoid receptor also blocked the effects of THC. Our findings suggest the THC promotes tumor growth by inhibiting antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway.

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Effect of the Psychoactive Metabolite of Marijuana, Δ9-Tetrahydrocannabinol (THC), on the Synthesis of Tumor Necrosis Factor by Human Large Granular Lymphocytes

Cited by 36 publications

References 0 publications

Evidence That 2-Arachidonoylglycerol but Not N-Palmitoylethanolamine or Anandamide Is the Physiological Ligand for the Cannabinoid CB2 Receptor

Evidence That 2-Arachidonoylglycerol but Not N-Palmitoylethanolamine or Anandamide Is the Physiological Ligand for the Cannabinoid CB2 Receptor

Cannabinoids enhance human B‐cell growth at low nanomolar concentrations

Δ-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway

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