Anandamide Suppresses Proliferation and Cytokine Release from Primary Human T-Lymphocytes Mainly via CB2 Receptors

Abstract

BackgroundAnandamide (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 CB1R and CB2R, making AEA a prominent member of the “endocannabinoid” family. Also immune cells express CB1 and CB2 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.Methodology/SignificanceIn 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-α and INF-γ 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 CB2R, since it could be mimicked by the CB2R selective agonist JWH-015, and could be blocked by the specific CB2R antagonist SR144528. Instead the selective CB1R agonist ACEA, or the selective CB1R 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.Conclusions/SignificanceOverall, 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 CB2R 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.

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

“…15 -17 In particular, AEA downregulates interleukin (IL)-2 transcription and secretion, reduces tumor necrosis factor (TNF)-and interferon (IFN)-production, induces lymphocyte apoptosis, and inhibits neutrophil recruitment at the site of inflammation. 17 Inflammatory stimuli may in turn control endocannabinoids by regulating their degradation. Indeed, lipopolysaccharide stimulation increases lymphocyte intracellular content of AEA by downregulating FAAH gene expression.…”

Endocannabinoid Signaling in Autism

“…Thus, the observed enhancement of CB 2 may be a negative feedback response aimed at counteracting the proinflammatory responses implicated in the pathogenesis of this neurobehavioral condition. In this context, it should be also recalled that AEA suppresses the release of proinflammatory cytokines from human lymphocytes through a CB 2 -mediated mechanism [112]. The main alterations of the eCB system in human patients and animal models of autism are summarized in Tables 1 and 2, respectively.…”

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