2-Arachidonoylglycerol modulates human endothelial cell/leukocyte interactions by controlling selectin expression through CB1 and CB2 receptors.

Published on Jun 1, 2014in The International Journal of Biochemistry & Cell Biology3.673
· DOI :10.1016/J.BIOCEL.2014.03.028
Valeria Gasperi28
Estimated H-index: 28
(Sapienza University of Rome),
D Evangelista6
Estimated H-index: 6
(Sapienza University of Rome)
+ 6 AuthorsMauro Maccarrone90
Estimated H-index: 90
(Sapienza University of Rome)
Abstract 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 1 h 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 1 h released the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) for up to 24 h. 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.
📖 Papers frequently viewed together
3 Authors (Sean Munro, ..., Muna Abu-Shaar)
4,070 Citations
5 Authors (Lisa A. Matsuda, ..., Tom I. Bonner)
4,195 Citations
4,617 Citations
#1Denise L. Faustman (Harvard University)H-Index: 40
#2Miriam Davis (Harvard University)H-Index: 14
The regulatory cytokine tumor necrosis factor (TNF) exerts its effects through two receptors: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy...
96 CitationsSource
#1Rodrigo Guabiraba (Glas.: University of Glasgow)H-Index: 23
#2Remo Castro Russo (UFMG: Universidade Federal de Minas Gerais)H-Index: 26
Last. Mauro M. Teixeira (UFMG: Universidade Federal de Minas Gerais)H-Index: 97
view all 9 authors...
Objective Angiogenesis depends on a complex interaction between cellular networks and mediators. The endocannabinoid system and its receptors have been shown to play a role in models of inflammation. Here, we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis.
18 CitationsSource
#1William J. Polacheck (MIT: Massachusetts Institute of Technology)H-Index: 17
#2Ioannis K. Zervantonakis (MIT: Massachusetts Institute of Technology)H-Index: 23
Last. Roger D. Kamm (MIT: Massachusetts Institute of Technology)H-Index: 108
view all 3 authors...
Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. I...
130 CitationsSource
The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ9-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid met...
199 CitationsSource
#1Andrea Chicca (University of Bern)H-Index: 21
#2Janine MarazziH-Index: 6
Last. Jürg GertschH-Index: 38
view all 4 authors...
Despite extensive research on the trafficking of anandamide (AEA) across cell membranes, little is known about the membrane transport of other endocannabinoids, such as 2-arachidonoylglycerol (2-AG). Previous studies have provided data both in favor and against a cell membrane carrier-mediated transport of endocannabinoids, using different methodological approaches. Because AEA and 2-AG undergo rapid and almost complete intracellular hydrolysis, we employed a combination of radioligand assays an...
98 CitationsSource
#1Lucy A. Coupland (ANU: Australian National University)H-Index: 9
#2Beng H. ChongH-Index: 66
Last. Christopher R. ParishH-Index: 73
view all 3 authors...
The prometastatic role of platelets has long been recognized with proposed mechanisms of action including shielding tumor cells from natural killer (NK) cell destruction and aiding endothelial attachment and extravasation of tumor cells with platelet P-selectin being implicated in these processes. However, many aspects of the prometastatic function of platelets remain unclear. In this study, we used mouse models of metastatic breast cancer and melanoma to investigate the platelet effect, focusin...
111 CitationsSource
#1Chan-Hee Jung (SCH: Soonchunhyang University)H-Index: 23
#2Bo-Yeon Kim (SCH: Soonchunhyang University)H-Index: 16
Last. Ji-Oh Mok (SCH: Soonchunhyang University)H-Index: 14
view all 6 authors...
Background Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. In addition, the autonomic imbalance is associated with cardiovascular disease (CVD) in diabetes. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, tumor necrosis factor-alpha (TNF-alpha), adiponectin...
34 CitationsSource
#1Janine Marazzi (University of Bern)H-Index: 6
#2Jonas Kleyer (University of Bern)H-Index: 3
Last. Jürg Gertsch (University of Bern)H-Index: 38
view all 4 authors...
The major endocannabinoids (ECs) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) and related N-ethanolamines act as full and partial agonists at CB(1), CB(2), GPR55, PPAR and TRPV1 receptors to various degrees. These receptors are also expressed in immune cells like monocytes/macrophages where they regulate different cellular processes. In this study, potentially bioactive lipids in fetal bovine sera (FBS) were quantified by GC/MS. We found that several commercial FBS contain EC...
32 CitationsSource
#1Simona Pisanti (UNISA: University of Salerno)H-Index: 28
#2Paola Picardi (UNISA: University of Salerno)H-Index: 14
Last. Maurizio Bifulco (UNISA: University of Salerno)H-Index: 56
view all 11 authors...
In this study we investigated the role of CB1 receptor signaling in angiogenesis and the therapeutic exploitation of CB1 inactivation as an antiangiogenic strategy. We started from the observation that CB1 receptor expression is induced during angiogenesis and that the endocannabinoid anandamide stimulated bFGF-induced angiogenesis in the nanomolar physiologic range. To define the functional involvement of CB1 receptor signaling during angiogenesis, 2 different strategies have been carried out: ...
48 CitationsSource
#1Jorge I. Alvarez (UdeM: Université de Montréal)H-Index: 29
#2Romain Cayrol (UdeM: Université de Montréal)H-Index: 18
Last. Alexandre Prat (UdeM: Université de Montréal)H-Index: 71
view all 3 authors...
Abstract The delicate microenvironment of the central nervous system (CNS) is protected by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCB). These barriers function in distinct CNS compartments and their anatomical basis lay on the junctional proteins present in endothelial cells for the BBB and in the choroidal epithelium for the BCB. During neuroinflammatory conditions like multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE)...
210 CitationsSource
Cited By31
#1Kaushalya Amunugama (SLU: Saint Louis University)
#2Daniel P. Pike (SLU: Saint Louis University)H-Index: 2
Last. David A. Ford (SLU: Saint Louis University)H-Index: 45
view all 3 authors...
Sepsis, defined as the dysregulated immune response to an infection leading to organ dysfunction, is one of the leading causes of mortality around the globe. Despite the significant progress in delineating the underlying mechanisms of sepsis pathogenesis, there are currently no effective treatments or specific diagnostic biomarkers in the clinical setting. The perturbation of cell signaling mechanisms, inadequate inflammation resolution, and energy imbalance, all of which are altered during seps...
#1Oindrila Rahaman (IICB: Indian Institute of Chemical Biology)H-Index: 5
#2Dipyaman Ganguly (IICB: Indian Institute of Chemical Biology)H-Index: 18
Endocannabinoids are key bioactive components of the endocannabinoid system and the profound influence of endocannabinoids on the modulation of the immune system is being increasingly appreciated. The knowledge of endocannabinoid-immune cell crosstalk will pave the way to therapeutic implications of modulators of this pathway in autoimmune and chronic inflammatory disorders.Endocannabinoids seem to exert both anti-inflammatory and pro-inflammatory effects in specific contexts, based on specific ...
#1Ramsha Khan (Emory University)H-Index: 5
#2Kristal M. Maner-Smith (Emory University)H-Index: 6
Last. Crystal Naudin (Emory University)H-Index: 7
view all 6 authors...
Cardiometabolic syndrome encompasses intertwined risk factors such as hypertension, dyslipidemia, elevated triglycerides, abdominal obesity, and other maladaptive metabolic and inflammatory aberrations. As the molecular mechanisms linking cardiovascular disease and metabolic disorders are investigated, endocannabinoids have emerged as molecules of interest. The endocannabinoid system (ECS) of biologically active lipids has been implicated in several conditions, including chronic liver disease, o...
1 CitationsSource
#1Durga Shankar Sharma (University of Hyderabad)H-Index: 4
#2Indira Paddibhatla (University of Hyderabad)H-Index: 6
Last. Ravi Kumar Gutti (University of Hyderabad)H-Index: 15
view all 10 authors...
Abstract The endocannabinoid system (ECS) is a complex physiological network involved in creating homeostasis and maintaining human health. Studies of the last 40 years have shown that endocannabinoids (ECs), a group of bioactive lipids, together with their set of receptors, function as one of the most important physiologic systems in human body. ECs and cannabinoid receptors (CBRs) are found throughout the body: in the brain tissues, immune cells, and in the peripheral organs and tissues as wel...
1 CitationsSource
#1Lian-Jie Hou (Guangzhou Medical University)H-Index: 3
#2Mei-Ying XieH-Index: 2
Last. Guo-Jun Zhao (Guangzhou Medical University)H-Index: 5
view all 4 authors...
1 CitationsSource
#1Lian-Jie Hou (Guangzhou Medical University)H-Index: 3
#1J Jehle (University Hospital Bonn)H-Index: 3
Last. Georg Nickenig (University Hospital Bonn)H-Index: 53
view all 6 authors...
#1J Jehle (University Hospital Bonn)H-Index: 3
#2Lukas Eich (University Hospital Bonn)H-Index: 1
Last. Georg Nickenig (University Hospital Bonn)H-Index: 53
view all 10 authors...
Abstract Background Endothelial dysfunction promotes atherogenesis, vascular inflammation, and thrombus formation. Reendothelialization after angioplasty is required in order to prevent stent failure. Previous studies have highlighted the role of 2-arachidonoylglycerol (2-AG) in murine experimental atherogenesis and in human coronary artery disease. However, the impact of 2-AG on endothelial repair and leukocyte–endothelial cell adhesion is still unknown. Methods Endothelial repair was studied i...
5 CitationsSource
Last. Alana de Freitas PiresH-Index: 15
view all 0 authors...
#1Melanie Kienzl (Medical University of Graz)H-Index: 4
#2Julia Kargl (Medical University of Graz)H-Index: 20
Last. Rudolf Schicho (Medical University of Graz)H-Index: 28
view all 3 authors...
Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocanna...
6 CitationsSource
#1Zuzanna Zajkowska ('KCL': King's College London)H-Index: 7
#2Alessandra Borsini ('KCL': King's College London)H-Index: 12
Last. Carmine M. Pariante ('KCL': King's College London)H-Index: 108
view all 13 authors...
Abstract The endocannabinoid (eCB) system is one of the key players in immunoregulation, and reduced activity of the eCB system has been linked with depressive-like behaviours in animal studies and depression in clinical samples. There is a well-established link between immune activation and depression, such as following the administration of the pro-inflammatory cytokine, interferon-α (IFN-α), used to treat hepatitis C viral (HCV) infection. However, the role of peripheral endocannabinoids (eCB...
1 CitationsSource