2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL-60 cells.
2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Previously, we provided evidence that 2-arachidonoylglycerol, but not anandamide (N-arachidonoylethanolamine), is the true natural ligand for the cannabinoid receptors. In the present study, we examined in detail the effects of 2-arachidonoylglycerol on the production of chemokines in human promyelocytic leukemia HL-60 cells. We found that 2-arachidonoylglycerol induced a marked acceleration in the production of interleukin 8. The effect of 2-arachidonoylglycerol was blocked by treatment of the cells with SR144528, a cannabinoid CB2 receptor antagonist, indicating that the effect of 2-arachidonoylglycerol is mediated through the CB2 receptor. Augmented production of interleukin 8 was also observed with CP55940, a synthetic cannabinoid, and an ether-linked analog of 2-arachidonoylglycerol. On the other hand, neither anandamide nor the free arachidonic acid induced the enhanced production of interleukin 8. A similar effect of 2-arachidonoylglycerol was observed in the case of the production of macrophage-chemotactic protein-1. The accelerated production of interleukin 8 by 2-arachidonoylglycerol was observed not only in undifferentiated HL-60 cells, but also in HL-60 cells differentiated into macrophage-like cells. Noticeably, 2-arachidonoylglycerol and lipopolysaccharide acted synergistically to induce the dramatically augmented production of interleukin 8. These results strongly suggest that the CB2 receptor and its physiological ligand, i.e., 2-arachidonoylglycerol, play important regulatory roles such as stimulation of the production of chemokines in inflammatory cells and immune-competent cells. Detailed studies on the cannabinoid receptor system are thus essential to gain a better understanding of the precise regulatory mechanisms of inflammatory reactions and immune responses.
Kishimoto
Seishi
S
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195.
Kobayashi
Yuriko
Y
Oka
Saori
S
Gokoh
Maiko
M
Waku
Keizo
K
Sugiura
Takayuki
T
D016718:Arachidonic Acid / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology / Q000502:physiology*; D015152:Blotting, Northern; D002117:Calcitriol / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005989:Glycerides / Q000494:pharmacology / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors
D001095:Arachidonic Acids; C111835:CCL2 protein, human; D001892:Camphanes; D018932:Chemokine CCL2; D018925:Chemokines; D003511:Cyclohexanols; D063388:Endocannabinoids; D005989:Glycerides; D016209:Interleukin-8; D008070:Lipopolysaccharides; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D016718:Arachidonic Acid; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; D002117:Calcitriol; C078814:anandamide