Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors

• Published in: PloS one Vol. 5; no. 1; p. e8688
• Main Authors: Cencioni, Maria Teresa, Chiurchiù, Valerio, Catanzaro, Giuseppina, Borsellino, Giovanna, Bernardi, Giorgio, Battistini, Luca, Maccarrone, Mauro
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.01.2010; Public Library of Science (PLoS)
• Subjects: Anandamide; Arachidonic Acids - pharmacology; Base Sequence; Bornanes - pharmacology; Brain; Brain research; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; CD4 antigen; Cell Biology; Cell Proliferation - drug effects; Cytokines; Cytokines - metabolism; Cytometry; Cytotoxicity; Dendritic cells; DNA Primers; Endocannabinoids; Enzyme-Linked Immunosorbent Assay; Fatty acids; Flow Cytometry; Glycerol; Humans; Immune system; Immunology; Immunology/Immunomodulation; Immunology/Leukocyte Activation; Immunosuppression; Immunosuppressive agents; Inflammation; Interleukin 17; Interleukin 2; Ligands; Lipids; Lymphocytes; Lymphocytes T; Machinery and equipment; Metabolism; Microscopy, Confocal; Modulation; Multiple sclerosis; Piperidines - pharmacology; Polyunsaturated Alkamides - pharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - metabolism; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Sodium; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tissues; Tumor necrosis factor-α; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008688

Anandamide (AEA) is an endogenous lipid mediator that exerts several effects in the brain as well as in peripheral tissues. These effects are mediated mainly by two types of cannabinoid receptors, named CB(1)R and CB(2)R, making AEA a prominent member of the "endocannabinoid" family. Also immune cells express CB(1) and CB(2) receptors, and possess the whole machinery responsible for endocannabinoid metabolism. Not surprisingly, evidence has been accumulated showing manifold roles of endocannabinoids in the modulation of the immune system. However, details of such a modulation have not yet been disclosed in primary human T-cells. In this investigation we used flow cytometry and ELISA tests, in order to show that AEA suppresses proliferation and release of cytokines like IL-2, TNF-alpha and INF-gamma from activated human peripheral T-lymphocytes. However, AEA did not exert any cytotoxic effect on T-cells. The immunosuppression induced by AEA was mainly dependent on CB(2)R, since it could be mimicked by the CB(2)R selective agonist JWH-015, and could be blocked by the specific CB(2)R antagonist SR144528. Instead the selective CB(1)R agonist ACEA, or the selective CB(1)R antagonist SR141716, were ineffective. Furthermore, we demonstrated an unprecedented immunosuppressive effect of AEA on IL-17 production, a typical cytokine that is released from the unique CD4+ T-cell subset T-helper 17. Overall, our study investigates for the first time the effects of the endocannabinoid AEA on primary human T-lymphocytes, demonstrating that it is a powerful modulator of immune cell functions. In particular, not only we clarify that CB(2)R mediates the immunosuppressive activity of AEA, but we are the first to describe such an immunosuppressive effect on the newly identified Th-17 cells. These findings might be of crucial importance for the rational design of new endocannabinoid-based immunotherapeutic approaches.