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)-tetrahydrocannab inol (THC) increased the expression of interleukin-2 (IL-2) receptor ( R) alpha and beta proteins and mRNAs in NKB61A2 cells, but decreased t he level of the gamma-chain message. The drug increased beta-chain mes sage stability rather than increased transcription. In the present stu dy, we examined the mechanism responsible for the drug-induced increas e in alpha-chain message in NKB61A2 cells. Nuclear run-on and mRNA sta bility studies showed THC increased the level of a gene transcription but had no effect on mRNA stability. Because expression of this gene i s regulated by nuclear factor (NF)-kappa B, we next tested the drug ef fect on the nuclear level of this protein using the electromobility sh ift assay. These studies showed a drug-induced increase in NF-kappa B activity. To link the increased nuclear factor activity with the THC-i nduced increase in IL-2R alpha message, antisense oligodeoxynucleotide s were used to inhibit expression of the RelA component of NF-kappa B. These results showed anti-RelA antisense eliminated the cannabinoid-i nduced 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 sugge st that THC treatment of NKB61A2 cells increases IL-2R alpha gene tran scription by increasing the nuclear level of NF-kappa B through a mech anism involving cannabinoid receptor type 1 expression.