Induction of Interleukin-2 Receptor α Gene by Δ 9 -Tetrahydrocannabinol Is Mediated by Nuclear Factor κB and CB1 Cannabinoid Receptor

Abstract

Previously, we reported that the cannabinoid Δ⁹-tetrahydrocannabinol (THC) increased the expression of interleukin-2 (IL-2) receptor (R) α and β proteins and mRNAs in NKB61A2 cells, but decreased the level of the γ-chain message. The drug increased β-chain message stability rather than increased transcription. In the present study, we examined the mechanism responsible for the drug-induced increase in α-chain message in NKB61A2 cells. Nuclear run-on and mRNA stability studies showed THC increased the level of α gene transcription but had no effect on mRNA stability. Because expression of this gene is regulated by nuclear factor (NF)-κB, 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-κB activity. To link the increased nuclear factor activity with the THC-induced increase in IL-2Rα message, antisense oligodeoxynucleotides were used to inhibit expression of the RelA component of NF-κB. These results showed anti-RelA antisense eliminated the cannabinoid-induced upregulation of both α mRNA and RelA protein. Furthermore, inhibition of the cannabinoid receptor type 1 with antisense oligomers also eliminated the drug effect on the α message. These results suggest that THC treatment of NKB61A2 cells increases IL-2Rα gene transcription by increasing the nuclear level of NF-κB through a mechanism involving cannabinoid receptor type 1 expression.