2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-α production in murine macrophages, and in mice

Gallily, Ruth; Breuer, Aviva; Mechoulam, Raphael

doi:10.1016/s0014-2999(00)00653-1

Cited by 155 publications

(94 citation statements)

References 6 publications

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“…Although the structurally unrelated endogenous cannabinoid 2-AG is able to inhibit ROS formation in vitro [154], when considering its in vivo anti-inflammatory effect cognitive decline susceptibility to neurodegenerative diseases repair of age-related deficits Figure 1. Accumulation of damaged macromolecules, organelle deficits lead to impairment in neuronal functions and neuroinflammation.…”

Section: The Cannabinoid System Modulates Age-related Molecular and Cmentioning

confidence: 99%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

120

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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, proageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brainderived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

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Section: The Cannabinoid System Modulates Age-related Molecular and Cmentioning

confidence: 99%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

120

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“…The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in various (patho)physiological processes and exerts numerous beneficial actions (ranging from pain modulation to reduction of anxiety) (5)(6)(7)(8)(9)(10)(11). The activity of this bioactive lipid depends on its endogenous levels, tightly controlled by the 2-AG hydrolyzing enzymes (12).…”

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confidence: 99%

Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6

Alhouayek

Masquelier

Cani

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

135

129

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Proinflammatory macrophages are key mediators in several pathologies; thus, controlling their activation is necessary. The endocannabinoid system is implicated in various inflammatory processes. Here we show that in macrophages, the newly characterized enzyme α/β-hydrolase domain 6 (ABHD6) controls 2-arachidonoylglycerol (2-AG) levels and thus its pharmacological effects. Furthermore, we characterize a unique pathway mediating the effects of 2-AG through its oxygenation by cyclooxygenase-2 to give rise to the anti-inflammatory prostaglandin D 2 -glycerol ester (PGD 2 -G). Pharmacological blockade of cyclooxygenase-2 or of prostaglandin D synthase prevented the effects of increasing 2-AG levels by ABHD6 inhibition in vitro, as well as the 2-AG-induced increase in PGD 2 -G levels. Together, our data demonstrate the physiological relevance of the interaction between the endocannabinoid and prostanoid systems. Moreover, we show that ABHD6 inhibition in vivo allows for fine-tuning of 2-AG levels in mice, therefore reducing lipopolysaccharide-induced inflammation, without the characteristic central side effects of strong increases in 2-AG levels obtained following monoacylglycerol lipase inhibition. In addition, administration of PGD 2 -G reduces lipopolysaccharide-induced inflammation in mice, thus confirming the biological relevance of this 2-AG metabolite. This points to ABHD6 as an interesting therapeutic target that should be relevant in treating inflammation-related conditions, and proposes PGD 2 -G as a bioactive lipid with potential anti-inflammatory properties in vivo.COX-2 | prostaglandin synthase | glyceryl prostaglandin | FAAH | anandamide

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“…They also demonstrated that 2-AG suppressed the interleukin-2 (IL-2) gene expression in murine T lymphocytes by down-regulating a nuclear factor. 31) As for macrophages, Gallily et al 32) reported that 2-AG suppressed the production of TNF-a in lipopolysaccharide (LPS)-stimulated mouse macrophages. Chang et al 33) demonstrated that 2-AG inhibited the production of IL-6 in LPS-stimulated J774 macrophage-like cells.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, several investigators suggested that the CB2 receptor and 2-AG play suppressive roles in inflammatory reactions and immune responses. [30][31][32][33] It is essential to determine whether 2-AG stimulates or suppresses inflammatory reactions and immune responses in order to fully elucidate the physiological significance of 2-AG in the immune system.…”

mentioning

confidence: 99%

2-Arachidonoylglycerol Enhances the Phagocytosis of Opsonized Zymosan by HL-60 Cells Differentiated into Macrophage-Like Cells

Gokoh

Kishimoto

Oka

et al. 2007

Biological & Pharmaceutical Bulletin

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2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). While evidence is accumulating that the CB1 receptor plays important regulatory roles in various nervous tissues and cells, the physiological roles of the CB2 receptor, which is abundantly expressed in the immune system, are yet to be determined. In this study, we examined in detail the effect of 2-arachidonoylglycerol on the phagocytosis of opsonized zymosan by HL-60 cells that had differentiated into macrophage-like cells. We found that the addition of 2-arachidonoylglycerol augmented the phagocytosis of opsonized zymosan by the differentiated HL-60 cells. The effect was observed from 1 nM and increased with increasing concentrations of 2-arachidonoylglycerol. Treatment of the cells with SR144528 or pertussis toxin abolished the effect of 2-arachidonoylglycerol, indicating that the CB2 receptor and Gi/o are involved in the augmented phagocytosis. Phosphatidylinositol 3-kinase and extracellular signal-regulated kinase were also suggested to be involved; treatment of the cells with wortmannin or PD98059 abrogated the 2-arachidonoylglycerol-augmented phagocytosis. These results strongly suggest that 2-arachidonoylglycerol, derived from stimulated inflammatory cells, has an important role in augmenting the phagocytosis of invading microorganisms by macrophages/monocytes thereby stimulating inflammatory reactions and immune responses.

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2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-α production in murine macrophages, and in mice

Cited by 155 publications

References 6 publications

The endocannabinoid system in normal and pathological brain ageing

The endocannabinoid system in normal and pathological brain ageing

Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6

2-Arachidonoylglycerol Enhances the Phagocytosis of Opsonized Zymosan by HL-60 Cells Differentiated into Macrophage-Like Cells

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