CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways.
Recruitment of leukocytes to inflammatory sites is crucial in the pathogenesis of chronic inflammatory diseases. The aim of this study was to investigate if activation of CB2 cannabinoid receptors would modulate the chemotactic response of human monocytes. Human monocytes treated with the CB2 agonist JWH-015 for 12-18 h showed significantly reduced migration to chemokines CCL2 and CCL3, associated with reduced mRNA and surface expression of their receptors CCR2 and CCR1. The induction of ICAM-1 in response to IFN-gamma was inhibited by JWH-015. Moreover, JWH-015 cross-desensitized human monocytes for migration in response to CCL2 and CCL3 by its own chemoattractant properties. The CB2-selective antagonist SR-144528, but not the CB1 antagonist SR-147778, reversed JWH-015-induced actions, whereas the CB2 agonist JWH-133 mimicked the effects of JWH-015. The investigation of underlying pathways revealed the involvement of phosphatidylinositol 3-kinase/Akt and ERK1/2 but not p38 MAPK. In conclusion, selective activation of CB2 receptors modulates chemotaxis of human monocytes, which might have crucial effects in chronic inflammatory disorders such as atherosclerosis or rheumatoid arthritis.
Montecucco
Fabrizio
F
Division of Cardiology, Foundation for Medical Researches, University Hospital, Geneva, Switzerland.
Burger
Fabienne
F
Mach
François
F
Steffens
Sabine
S
D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000494:pharmacology; D054405:Chemokine CCL3 / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D009000:Monocytes / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D019707:Receptors, Chemokine; D018799:Intercellular Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; C402944:JHW 015