Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression

Abstract

Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially. Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood and can be broadly categorized into four pathways: apoptosis, inhibition of proliferation, suppression of cytokine and chemokine production and induction of T regulatory cells (T regs). Studies from our laboratory have focused on mechanisms of apoptosis induction by natural and synthetic cannabinoids through activation of CB2 receptors. In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects.

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

“…15 -17 Cannabinoids reduce the MHC class II expression on the surface of dendritic cells, hence affecting antigen presentation, and inhibit peripheral T-cell activation in response to lipopolysaccharide and anti-CD3 antibodies. 26,29,30 Based on these findings, several studies have focused on the use of cannabinoids for the treatment of immune-mediated diseases, both in experimental models and humans. 29 As the dysregulated proinflammatory response observed in IBD pathogenesis is characterized by a T helper cell type (Th)1 / Th17 immune profile, 31 we explored the influence of endocannabinoids on T cell-mediated gut inflammation, by investigating the in vitro and ex vivo effects of the synthetic non-hydrolysable AEA analog MAEA on proinflammatory cytokine production by anti-CD3 / CD28-stimulated LPMCs, CD3 + LPMCs, and biopsies from inflamed IBD mucosa.…”

CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura

“…For the first time, we showed an association between ITP and a functional variant of the CNR2 gene, encoding for a protein known to affect immune function. The rationale for our study was based on: i) the linkage between the 1p36 locus, where CNR2 maps, and sever- 18,19 Furthermore, immunomodulation by cannabinoids is totally absent in mice lacking the CB2 receptor. 20 The Q63R CB2 variant results in the amino acid substitution of a polar, uncharged, glutamine with a positively charged arginine.…”

Selective capacity of metreleptin administration to reconstitute CD4 + T-cell number in females with acquired hypoleptinemia

“…ARNT is a key component in the elimination of dioxins, well known to be involved in autoimmune disease susceptibility, generation of Th17 and regulatory T (Treg) cells, and protection from infections (23,24). The BCL-2-like-11 protein, which is an apoptosis facilitator, and the cannabinoid receptor 2 (Cnr2), which is known to inhibit macrophage-induced inflammation, were both down-regulated (25). Finally, we also observed the down-modulation of the TGF-β receptor-associated protein-1 (TGFBRAP-1), which plays a role in the TGF-β/activin signaling pathways known to be involved in the control of immune responses and down-modulation of inflammation.…”