CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents.
Cannabinoids are known to interact with CB1 and CB2 receptors expressed in the nervous and immune system, respectively, and mediate a wide range of effects, including anti-inflammatory properties. However, cannabinoids that bind CB1 are also psychoactive thereby limiting their clinical use. In this study, we investigated the immunosuppressive properties of JWH-015, a synthetic CB2-selective agonist. We found that JWH-015 triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through induction of apoptosis. JWH-015 induced cross-talk between extrinsic and intrinsic pathways of apoptosis involving caspase-8, caspase-9, and caspase-3 as well as loss of mitochondrial membrane potential. Finally, administration of JWH-015 in vivo caused thymic atrophy, apoptosis, and decreased peripheral T cell response to mitogens. Together, this study suggests that CB2-selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.
Lombard
Catherine
C
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 6311 Garners Ferry Road, Building 28, Columbia, SC 29208, USA.
Nagarkatti
Mitzi
M
Nagarkatti
Prakash
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism*; D013154:Spleen / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology
D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007211:Indoles; D008024:Ligands; D008934:Mitogens; D043885:Receptor, Cannabinoid, CB2; C402944:JHW 015