2-Arachidonoylglycerol Induces the Migration of HL-60 Cells Differentiated into Macrophage-like Cells and Human Peripheral Blood Monocytes through the Cannabinoid CB2 Receptor-dependent Mechanism

Abstract

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2) and has beenshown to exhibit a variety of cannabimimetic activities in vitro and in vivo. Recently, we proposed that 2-arachidonoylglycerol is the true endogenous ligand for the cannabinoid receptors, and both receptors (CB1 and CB2) are primarily 2-arachidonoylglycerol receptors. The CB1 receptor is assumed to be involved in the attenuation of neurotransmission. On the other hand, the physiological roles of the CB2 receptor, which is abundantly expressed in several types of leukocytes such as macrophages, still remain unknown. In this study, we examined the effects of 2-arachidonoylglycerol on the motility of HL-60 cells differentiated into macrophage-like cells. We found that 2-arachidonoylglycerol induces the migration of differentiated HL-60 cells. The migration induced by 2-arachidonoylglycerol was blocked by treatment of the cells with either SR144528, a CB2 receptor antagonist, or pertussis toxin, suggesting that the CB2 receptor and G i /G o are involved in the 2-arachidonoylglycerol-induced migration. Several intracellular signaling molecules such as Rho kinase and mitogen-activated protein kinases were also suggested to be involved. In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, failed to induce the migration. The 2-arachidonoylglycerol-induced migration was also observed for two other types of macrophage-like cells, the U937 cells and THP-1 cells, as well as human peripheral blood monocytes. These results strongly suggest that 2-arachidonoylglycerol induces the migration of several types of leukocytes such as macrophages/monocytes through a CB2 receptor-dependent mechanism thereby stimulating inflammatory reactions and immune responses.

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

“…Consistent with their anti-inflammatory role observed in CB 2 receptor-deficient mice, endocannabinoids can inhibit chemotaxis and the production of cytokines ex vivo (15)(16)(17)(18)(19)(20). However, an increasing body of evidence also demonstrates that like eicosanoids, endocannabinoids can stimulate proinflammatory functions of myeloid cells, such as cell adhesion, chemotaxis, phagocytosis, and the release of cytokines (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

A Glial Endogenous Cannabinoid System Is Upregulated in the Brains of Macaques with Simian Immunodeficiency Virus-Induced Encephalitis

“…Conversely, two groups have shown recently that CB 2 activation also promotes microglial migration and proliferation (Walter et al, 2003;Carrier et al, 2004). Furthermore, CB 2 activation enhances human macrophage-like and peripheral blood monocyte migration after CB 2 activation (Derocq et al, 2000;Kishimoto et al, 2003).…”

Involvement of the Cannabinoid CB2 Receptor and Its Endogenous Ligand 2-Arachidonoylglycerol in Oxazolone-Induced Contact Dermatitis in Mice

“…We found that 2-AG induces the following: 1) a Ca 2ϩ transient in HL-60 cells (21); 2) the activation of p42/44 MAPK (22); 3) augmented production of chemokines such as IL-8 in HL-60 cells (23); and 4) migration of HL-60 cells that had differentiated into macrophage-like cells (24), human NK cells (25), and eosinophils (26), through CB2 receptorand Gi/o-dependent mechanisms. Several investigators also demonstrated that 2-AG induced the migration of mouse splenocytes (27), microglia cells (28), and dendritic cells (29).…”