delta 9-Tetrahydrocannabinol enhances the secretion of interleukin 1 from endotoxin-stimulated macrophages

Interleukin (IL) 1 is a pleiotropic cytokine and an important mediator of various physiological responses including the acute phase response, inflammation, lymphocyte function and certain central nervous system responses. Because delta 9-tetrahydrocannabinol (THC) treatment also has been reported to affect these physiological responses, we tested the drug effect on IL1 production and secretion. Addition of THC to endotoxin (ETX)-treated murine, resident peritoneal macrophage cultures increased, in a dose-dependent manner, supernatant IL1 activity over ETX only treatment. Treatment with THC alone had no effect. Enzyme-linked immunosorbent assay studies and specific antibody neutralization studies demonstrated both IL1 alpha and IL1 beta were increased by drug treatment. The steady-state levels of cellular IL1 alpha and IL1 beta mRNAs, determined by Northern blotting and reverse transcription-polymerase chain reaction, were unchanged, suggesting the possibility THC was not increasing IL1 production. To examine this possibility further, ETX-activated macrophages, pulsed-labeled with 35S-methionine, were chased for 2, 4 and 6 hr in the presence of THC and the levels of the various IL1 bioforms determined by immunoprecipitation. These results showed THC treatment had no effect on the level of ETX-induced intracellular promature IL1 alpha and IL1 beta proteins; however, a THC-induced increase and prolongation of release of promature IL1 alpha and mature IL1 beta were observed. The immunoprecipitation results were confirmed by studies examining supernatant bioactivity. These results suggest THC augments the ETX-induced processing of IL1 beta and release of IL1 alpha rather than increasing the cellular production of IL1 protein.(ABSTRACT TRUNCATED AT 250 WORDS)