title: Cannabinoids inhibit the activation of ERK MAPK in PMA/Io-stimulated mouse splenocytes.
abstract: The mechanism of action of immune suppression by cannabinoids involves suppression of interleukin-2 (IL-2) production in phorbol ester plus calcium ionophore (PMA/Io)-stimulated lymphocytes. This decrease in IL-2 was due to inhibition of activator protein-1 (AP-1) and nuclear factor of activated T cells (NF-AT) transcription factors, both of which depend on proteins that are regulated by the extracellular signal-regulated kinase subgroup of the mitogen-activated protein kinases (ERK MAPK). Thus, the objective of the present study was to characterize the effects of cannabinoid compounds on ERK MAPK under conditions where IL-2 expression was suppressed. Using the MEK inhibitor PD098059 in order to assess the role of ERK MAPK in PMA/Io-stimulated splenocytes (SPLC), it was determined that IL-2 production and expression of c-fos and c-jun nuclear protein expression depended on activation of ERK MAPK. In response to PMA/Io, expression of nuclear phosphorylated ERK MAPK was rapidly induced, peaked at approximately 15 min, and was sustained for up to 240 min. Pretreatment with cannabinol (CBN) inhibited expression of phosphorylated ERK MAPK at several time points up to 240 min post cellular activation. Furthermore, WIN-55212-2, a synthetic cannabinoid, inhibited expression of phosphorylated ERK MAPK at 240 min post cellular activation. CBN did not induce activation of ERK MAPK in the absence of PMA/Io. Collectively, these studies suggest that cannabinoid-induced inhibition of IL-2 in PMA/Io-stimulated splenocytes might be due, in part, to inhibition of ERK MAPK activation.
authors.affiliation: Department of Pharmacology and Toxicology, 315 National Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Faubert Kaplan
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002186:Cannabinoids / Q000494:pharmacology*; D002478:Cells, Cultured; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D007476:Ionophores / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D009687:Nuclear Proteins / Q000096:biosynthesis; D010703:Phorbol Esters / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology
chemical_list: D002186:Cannabinoids; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007476:Ionophores; D009687:Nuclear Proteins; D010703:Phorbol Esters; D020928:Mitogen-Activated Protein Kinases