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.
Jan
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Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.
Kaminski
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D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D007376:Interleukin-2 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D002186:Cannabinoids; D007376:Interleukin-2; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases