2-Arachidonoylglycerol modulates human endothelial cell/leukocyte interactions by controlling selectin expression through CB1 and CB2 receptors.
Accumulated evidence points to a key role for endocannabinoids in cell migration, and here we sought to characterize the role of these substances in early events that modulate communication between endothelial cells and leukocytes. We found that 2-arachidonoylglycerol (2-AG) was able to initiate and complete the leukocyte adhesion cascade, by modulating the expression of selectins. A short exposure of primary human umbilical vein endothelial cells (HUVECs) to 2-AG was sufficient to prime them towards an activated state: within 1h of treatment, endothelial cells showed time-dependent plasma membrane expression of P- and E-selectins, which both trigger the initial steps (i.e., capture and rolling) of leukocyte adhesion. The effect of 2-AG was mediated by CB1 and CB2 receptors and was long lasting, because endothelial cells incubated with 2-AG for 1h released the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) for up to 24h. Consistently, TNF-α-containing medium was able to promote leukocyte recruitment: human Jurkat T cells grown in conditioned medium derived from 2-AG-treated HUVECs showed enhanced L-selectin and P-selectin glycoprotein ligand-1 (PSGL1) expression, as well as increased efficiency of adhesion and trans-migration. In conclusion, our in vitro data indicate that 2-AG, by acting on endothelial cells, might indirectly promote leukocyte recruitment, thus representing a potential therapeutic target for treatment of diseases where impaired endothelium/leukocyte interactions take place.
Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.
Valeria
V
Gasperi
Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.
Daniela
D
Evangelista
Faculty of Veterinary Medicine, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy; European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
Valerio
V
Chiurchiù
European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
Fulvio
F
Florenzano
Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.
Isabella
I
Savini
Faculty of Veterinary Medicine, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy; European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
Sergio
S
Oddi
Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.
Luciana
L
Avigliano
Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy. Electronic address: catani@uniroma2.it.
Maria Valeria
MV
Catani
European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy; Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy. Electronic address: m.maccarrone@unicampus.it.
Mauro
M
Maccarrone
D001095:Arachidonic Acids / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D063388:Endocannabinoids / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005989:Glycerides / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019169:Jurkat Cells; D019007:P-Selectin / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D019087:Selectins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001095:Arachidonic Acids; D019040:E-Selectin; D063388:Endocannabinoids; D005989:Glycerides; D019007:P-Selectin; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D019087:Selectins; D014409:Tumor Necrosis Factor-alpha; C094503:glyceryl 2-arachidonate
Endocannabinoids; Endothelium/leucocyte interaction; Kinases; Selectins; TNF-α