Role of mitogen-activated protein kinases in the differential regulation of interleukin-2 by cannabinol

Cannabinoids can paradoxically regulate interleukin-a (IL-2) expression eit her positively or negatively. This study investigated the mechanism respons ible for cannabinol-mediated IL-2 modulation. In primary murine splenocytes and EL4.IL-2 T cells, the contrasting effects of cannabinol on IL-2 secret ion depended on the magnitude but not the mode of T-cell activation. Subopt imal activation of T cells in the presence of cannabinol produced an enhanc ement of IL-2 secretion, which was paralleled by an increase in nuclear pho spho-extracellular-regulated kinase (ERK) 1/2, In contrast, T cells activat ed with stimuli that were optimized to induce maximal IL-2 secretion elicit ed a marked suppression in the production of this cytokine when cultured in the presence of cannabinol, Moreover, cannabinol-mediated enhancement of I L-2 secretion by splenocytes was attenuated to various degrees by staurospo rine, Ro-31-8220, and KN93, These results suggest that the enhancement of I L-2 secretion by cannabinol is associated with an increase in ERK mitogen-a ctivated protein kinase, which is protein kinase C and calmodulin-kinase de pendent.