AP-1 activity is negatively regulated by cannabinol through inhibition of its protein components, c-fos and c-jun

Regulation of the activator protein-1 (AP-1) complex is very intricate beca use it involves phosphorylation state, protein-protein, and protein-DNA int eractions. in these studies, the regulation of AP-1 activity, with emphasis on c-fos and c-jun regulation, was investigated using cannabinol (CBN) in primary mouse splenocytes in vitro. Cannabinoid compounds exhibit immunosup pressive actions that are putatively mediated through Gi-protein coupled re ceptors that negatively regulate adenylate cyclase, However, recent studies suggest that cannabinoids modulate other signaling cascades. Indeed, we de monstrate that CBN inhibited binding to AP-1-containing sites from the inte rleukin-2 promoter. This inhibition of binding was, in part, due to decreas ed nuclear expression of c-fos and c-jun, We further determined that the, e ffects of CBN were due to posttranslational modifications of these phosphop roteins and showed that CBN inhibited the activation of ERK MAP kinases. Th us, cannabinoid-induced immunosuppression involves disruption of the ERK si gnaling cascade.