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cannabinoids and inflammation

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Inflammasomes in Chronic Inflammatory Disorders

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Ajulemic acid, a side-chain synthetic analog of Δ(8)-THC-11-oic acid, has been shown to induce apoptosis in human peripheral blood T lymphocytes via the intrinsic pathway at concentrations of 1, 3 and 10 μM [21]. In addition, the use of synthetic CB2 agonist JWH-015 treatment in vitro led to cell death via both the death-receptor pathway and the intrinsic pathway. When JWH-015 was administered in vivo, the antigen-specific response to Staphylococcal enterotoxin A was inhibited significantly [22].

It is important to note that, unlike in immune cells, cannabinoids can protect from apoptosis in nontransformed cells of the CNS, which can play a protective role in autoimmune conditions such as multiple sclerosis. Cannabinoids protect against apoptosis of oligodendrocytes via CB1 and CB2 receptors, by signaling through the PI3K/AKT pathway. In vivo and in vitro exposure to arachidonyl-2-ethylamide (ACEA) and WIN55,212-12 protected the cells, while pretreatment with CB1 receptor antagonist SR141716A and CB2 receptor antagonist SR144528 blocked the action of these cannabinoids [23]. In a different study by Jackson et al., 3D mouse brain aggregate cell cultures were compared between wild-type mice and CB1 receptor knockout mice. IFN-γ treatment led to decrease in the neurofilament-H expression in knockout cultures but not in wild-type cultures. In addition, caspase 3 activation was higher in knockout cultures, indicating a protective role of CB1 in neuronal cells [24].

Apoptotic effects of cannabinoids on immune cell populations

Other natural and synthetic cannabinoid compounds (CBD, AEA, ajulemic acid [AjA] and JWH-015), whose structures are depicted in Table 1 , have also been shown to induce apoptosis in murine and human T lymphocytes. Cannabidiol, the nonpsychoactive ingredient in cannabis, induced apoptosis in CD4 + and CD8 + T cells at 4–8-μM concentrations by increasing reactive oxygen species (ROS) production as well as caspase 3 and 8 activity [20].

In the small intestine, the involvement of CB1 receptors in the control of intestinal motility during croton oil-induced inflammation was recently demonstrated. Izzo et al. showed that pharmacological administration of cannabinoids is able to delay gastrointestinal transit in croton oil-treated mice [65]. It was further suggested that increased levels of CB1 receptor expression in inflamed jejuna may contribute to this protective effect. CB1 receptors were shown to modulate gastrointestinal motility during croton oil-induced inflammation in mice.

Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ 9 -tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.