Abstract
The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases.
Highlights
The endocannabinoid system (ECS) is quite ubiquitous in mammalian cells and, following transient or chronic perturbation of tissue homeostasis, it may have a regulatory role by its local activation and modulation of other chemical signals [1]
We reported for the first time an in vitro evaluation of a novel synthetic compound, JT11, which is shown to be a selective and high-affinity CB2R agonist [26]
We first tested its biological activity on Jurkat T lymphoblasts and its anti-inflammatory properties on human peripheral blood mononuclear cells (PBMCs), both mediated by the interaction with CB2R
Summary
The endocannabinoid system (ECS) is quite ubiquitous in mammalian cells and, following transient or chronic perturbation of tissue homeostasis, it may have a regulatory role by its local activation and modulation of other chemical signals [1]. This complex signaling system consists of cannabinoid receptors, their endogenous ligands (known as “endocannabinoids”), and the enzymes responsible for endocannabinoid biosynthesis, cellular uptake and catabolism [2]. Cannabinoid receptor 2 (CB2R) are the most extensively studied [3,4] Both belong to class A of G protein-coupled receptors (GPCRs) and are associated with Gi/o proteins that inhibit cyclic AMP (cAMP) production. CB2R is mainly expressed by leukocytes, in a variable manner depending on cell type, their activation state and stimuli to which they are subjected [7,8,9,10,11,12]
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