Abstract:
:Tetrahydrocannabinol (THC), a psychoactive component of marijuana, is known to exert cytotoxicity in immune cells. In the present study, we examined the cytotoxicity of Δ⁸-THC in mouse macrophage J774-1 cells and a possible involvement of cannabinoid receptors and stress-responsive mitogen-activated protein kinases (MAPKs) in the cytotoxic process. J774-1 cells were treated with Δ⁸-THC (0-20 μM) for up to 6 h. As measured by the MTT and LDH assays, Δ⁸-THC induced cell death of J774-1 cells in a concentration- and/or exposure time-dependent manner. Δ⁸-THC-induced cell damage was associated with vacuole formation, cell swelling, chromatin condensation, and nuclear fragmentation. The cytotoxic effect of Δ⁸-THC was significantly prevented by a caspase-1 inhibitor Ac-YVAD-cmk but not a caspase-3 inhibitor z-DEVD-fmk. The pretreatment with SR144528, a CB₂ receptor-selective antagonist, effectively suppressed Δ⁸-THC-induced cytotoxicity in J774-1 cells, which exclusively expressed CB₂ receptors as indicated by real-time polymerase chain reaction analysis. In contrast, AM251, a CB₁ receptor-selective antagonist, did not affect the cytotoxicity. Pertussis toxin and α-tocopherol significantly attenuated Δ⁸-THC-induced cytotoxicity suggesting that G(i/o) protein coupling signal transduction and oxidative stress are responsible for the cytotoxicity. Δ⁸-THC stimulated the phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) in J774-1 cells, which were effectively antagonized by the pretreatment with SR144528. In addition, SB203580, a p38 MARK inhibitor, significantly attenuated the cytotoxic effect of Δ⁸-THC, whereas SP600125, a JNK inhibitor, significantly enhanced the cytotoxicity. These results suggest that the cytotoxicity of Δ⁸-THC to J774-1 cells is exerted mediated through the CB₂ receptor followed by the activation of p38 MAPK.
journal_name
Toxicologyjournal_title
Toxicologyauthors
Yamaori S,Ishii H,Chiba K,Yamamoto I,Watanabe Kdoi
10.1016/j.tox.2013.10.007subject
Has Abstractpub_date
2013-12-15 00:00:00pages
254-61issue
2-3eissn
0300-483Xissn
1879-3185pii
S0300-483X(13)00281-3journal_volume
314pub_type
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