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

Cannabinoids can paradoxically regulate interleukin-2 (IL-2) expression either positively or negatively. This study investigated the mechanism responsible for cannabinol-mediated IL-2 modulation. In primary murine splenocytes and EL4.IL-2 T cells, the contrasting effects of cannabinol on IL-2 secretion depended on the magnitude but not the mode of T-cell activation. Suboptimal activation of T cells in the presence of cannabinol produced an enhancement of IL-2 secretion, which was paralleled by an increase in nuclear phospho-extracellular-regulated kinase (ERK) 1/2. In contrast, T cells activated with stimuli that were optimized to induce maximal IL-2 secretion elicited a marked suppression in the production of this cytokine when cultured in the presence of cannabinol. Moreover, cannabinol-mediated enhancement of IL-2 secretion by splenocytes was attenuated to various degrees by staurosporine, Ro-31-8220, and KN93. These results suggest that the enhancement of IL-2 secretion by cannabinol is associated with an increase in ERK mitogen-activated protein kinase, which is protein kinase C and calmodulin-kinase dependent.