Activation through Cannabinoid Receptors 1 and 2 on Dendritic Cells Triggers NF-κB-Dependent Apoptosis: Novel Role for Endogenous and Exogenous Cannabinoids in Immunoregulation

Abstract

The precise role of cannabinoid receptors (CB)1 and CB2, as well as endogenous ligands for these receptors, on immune cells remains unclear. In the current study, we examined the effect of endogenous and exogenous cannabinoids on murine bone marrow-derived dendritic cells (DCs). Addition of Δ9-tetrahydrocannabinol (THC), a major psychoactive component found in marijuana or anandamide, an endogenous cannabinoid, to DC cultures induced apoptosis in DCs. DCs expressed CB1 and CB2 receptors and the engagement of both receptors was necessary to trigger apoptosis. Treatment with THC induced caspase-2, -8, and -9 activation, cleavage of Bid, decreased mitochondrial membrane potential, and cytochrome c release, suggesting involvement of death-receptor and mitochondrial pathways. DCs from Bid-knockout mice were sensitive to THC-induced apoptosis thereby suggesting that Bid was dispensable. There was no induction of p44/p42 MAPK, p38 MAPK, or stress-activated protein/JNK pathway in THC-treated DCs. However, THC treatment induced phosphorylation of IκB-α, and enhanced the transcription of several apoptotic genes regulated by NF-κB. Moreover, inhibition of NF-κB was able to block THC-induced apoptosis in DCs. Lastly, in vivo treatment of mice with THC caused depletion of splenic DCs. Together, our study demonstrates for the first time that endogenous and exogenous cannabinoids may suppress the immune response through their ability to induce apoptosis in DCs.

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: Potential role for CB2-selective ligands as immunosuppressive agents

“…To this end, we demonstrated that administration of THC into mice caused a reduction in the cellularity of the thymus and spleen, and decreases the ability of T and B cells to divide upon activation, which correlated with induction of apoptosis [16]. Furthermore, a recent study from our laboratory demonstrated that THC or anandamide, an endogenous cannabinoid, can induce apoptosis in dendritic cells (DCs) in vitro and treatment of mice with THC caused depletion of splenic DCs [13]. While such studies on one hand suggest that abuse of marijuana or clinical use of THC in AIDS or cancer patients may cause an undesired effect namely immunosuppression.…”

“…Δ 9 -tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and other cannabinoids have been shown to be immunosuppressive both in vitro and in vivo, affecting macrophages, natural killer cells, B cells, T cells, mast cells and dendritic cells (DCs) [1,13,14]. It is generally believed that cannabinoids alter the immune functions through their ability to mediate an effect on cytokine production and to exert anti-proliferative properties [15] (Review).…”

“…While such studies on one hand suggest that abuse of marijuana or clinical use of THC in AIDS or cancer patients may cause an undesired effect namely immunosuppression. On the other hand, the ability of cannabinoids to suppress the immune functions can be potentially exploited for the treatment of inflammatory and autoimmune diseases by inhibiting the proliferative response of B and T cells, and by decreasing antigen-presentation by DCs [16] [13]. However, the clinical use of marijuana and cannabinoids such as THC is still very controversial due to the psychotropic side effect associated with the treatment.…”

Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria

“…Numerous studies have shown that THC can modulate the functions of immune cells (7). More recently, we reported that the immunosuppressive property of THC can be attributed, at least in part, to its ability to induce apoptosis in T cells and dendritic cells through ligation of CB2 receptors and that the latter was regulated by activation of nuclear factor-nB (8), recruiting both intrinsic and extrinsic pathways of apoptosis. Interestingly, we also found that THC and other cannabinoids could induce apoptosis in transformed murine and human T cells (9), including primary acute lymphoblastic human leukemia cells, and furthermore that the treatment of mice bearing a T-cell leukemia with THC could cure f25% of the mice (10).…”

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

“…Moreover, the cannabinoid system exerts a control function over the immune system. Activation of CB2 and probably also CB1 receptor, enhances migration and adhesion of immune cells, decreases the release of proinflammatory cytokines (22), and induces apoptosis in dendritic cells (23). These data led to the assumption that endocannabinoid signaling plays a role in the development of neurodegenerative diseases (24) and could be a potential target for novel pharmacotherapies (25).…”