A COX-2 metabolite of the endogenous cannabinoid, 2-arachidonyl glycerol, mediates suppression of IL-2 secretion in activated Jurkat T cells.
Previous studies from this laboratory have demonstrated that a COX-2 metabolite of the endogenous cannabinoid, 2-arachidonyl glycerol (2-AG), inhibits IL-2 secretion in activated T cells through PPARgamma activation independent of the cannabinoid receptors, CB1/CB2. Because numerous cyclooxygenase (COX) products have been shown to activate PPARgamma, the primary purpose of the present studies was to determine the role of COX metabolism in the inhibition of IL-2 secretion by 2-AG. Pretreatment with nonselective and COX-2-specific inhibitors completely abrogated 2-AG-mediated suppression of IL-2 secretion. In contrast, pretreatment with COX-1-specific inhibitors had no effect upon 2-AG-mediated inhibition of IL-2 secretion. Interestingly, the current studies also demonstrate that while the potency of 2-AG is comparable between human Jurkat T cells and murine splenocytes, anandamide (AEA) is markedly more potent in suppressing IL-2 production in Jurkat T cells compared to murine splenocytes. Additionally, the present studies also demonstrate that COX-2 protein is readily detectable in resting Jurkat T cells, which is in contrast to resting murine splenocytes in which COX-2 protein is virtually undetectable. Furthermore, COX-2 protein and mRNA levels are significantly increased over basal levels by 2h following activation of Jurkat cells, whereas increases in COX-2 protein in murine splenocytes are not observed until 4h after cellular activation. These studies suggest that the potency of AEA in the suppression of IL-2 secretion may correlate with COX-2 protein levels in different T cell models. The present studies are also significant in that they demonstrate 2-AG-mediated inhibition of IL-2 secretion is dependent upon COX-2 metabolism.
Rockwell
Cheryl E
CE
Department of Pharmacology & Toxicology and the Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
Raman
Priyadarshini
P
Kaplan
Barbara L F
BL
Kaminski
Norbert E
NE
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D063388:Endocannabinoids; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D005989:Glycerides; D007376:Interleukin-2; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2