Induction of interleukin-2 receptor alpha gene by Delta(9)-tetrahydrocannabinol is mediated by nuclear factor kappa B and CB1 cannabinoid receptor

Previously, we reported that the cannabinoid Delta(9)-tetrahydrocannabinol (THC) increased the expression of interleukin-2 (IL-2) receptor (R) alpha and beta proteins and mRNAs in NKB61A2 cells, but decreased the level of the gamma-chain message. The drug increased beta-chain message stability rather than increased transcription. In the present study, we examined the mechanism responsible for the drug-induced increase in alpha-chain message in NKB61A2 cells. Nuclear run-on and mRNA stability studies showed THC increased the level of a gene transcription but had no effect on mRNA stability. Because expression of this gene is regulated by nuclear factor (NF)-kappa B, we next tested the drug effect on the nuclear level of this protein using the electromobility shift assay. These studies showed a drug-induced increase in NF-kappa B activity. To link the increased nuclear factor activity with the THC-induced increase in IL-2R alpha message, antisense oligodeoxynucleotides were used to inhibit expression of the RelA component of NF-kappa B. These results showed anti-RelA antisense eliminated the cannabinoid-induced upregulation of both alpha mRNA and RelA protein. Furthermore, inhibition of the cannabinoid receptor type 1 with antisense oligomers also eliminated the drug effect on the a message. These results suggest that THC treatment of NKB61A2 cells increases IL-2R alpha gene transcription by increasing the nuclear level of NF-kappa B through a mechanism involving cannabinoid receptor type 1 expression.