CB2 cannabinoid receptor agonist, JWH015 triggers apoptosis in immune cells : potential role for CB2 selective ligands as immunosuppressive agents
(2005) 44th Annual meeting of the Society of Toxicology — Location: New Orleans, Louisian, USA
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- Abstract
- Cells of the immune system uniquely express a cannabinoid receptor designated CB2, whose precise function remains unclear. Delta-9-tetrahydrocannabinol (THC), a major psychoactive component found in marijuana and other cannabi-noids that interact with both CB1 and CB2 receptors are known to induce apopto-sis in immune cells and cause immunosuppression. Such studies suggested the pos-sible use of cannabinoids as anti-inflammatory/immunosuppressive agents. However, cannabinoids that bind CB1 receptors are also psychoactive thereby lim-iting their clinical use. In the current study, we therefore investigated whether the synthetic CB2-selective agonist JWH015, devoid of psychoactivity, would mediate apoptosis and cause immunomodulation in vivo. We found that JWH015 inhib-ited the proliferative response of splenocytes to T and B cell mitogens in vitro which correlated with induction of apoptosis. In addition, JWH015 trigerred apoptosis in thymocytes in vitro. Mechanisms of apoptosis revealed that JWH015 caused release of cytochrome c and Smac, and cleavage of capsase-8, caspase-9, caspase-3 and Bid, as well as caused loss of mitochondrial membrane potential (∆ψm). Use of caspase inhibitors showed that JWH015 induced apoptosis through cross-talk between the extrinsic (death receptor) and the intrinsic (mitochondrial) pathways of apoptosis. Finally, administration of JWH015 into C57BL/6 mice caused thymic atrophy and apoptosis as well as decreased peripheral T cell response to mitogens. Together, this study suggests for the first time that CB2 selective agonists can induce apoptosis in immune cells and cause immunosuppression. Thus, such cannabinoids may serve as novel anti-inflammatory/immunosuppressive agents and would be ideal candi-dates for clinical due to lack of psychotropic effects.
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Lombard, C., Nagarkatti, M., & Nagarkatti, P. (2005). CB2 cannabinoid receptor agonist, JWH015 triggers apoptosis in immune cells : potential role for CB2 selective ligands as immunosuppressive agents. Toxicological Sciences, 84(1 supplement), 74. https://hdl.handle.net/2078.5/182050 (Original work published 2005)