Document Detail

A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes.
MedLine Citation:
PMID:  15284281     Owner:  NLM     Status:  MEDLINE    
Arachidonyl ethanolamine, which is commonly known as anandamide, was the first endogenous compound to be identified that binds to the cannabinoid receptors. Anandamide mimics many of the physiological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including hypothermia, antinociception, immobility, catalepsy, and immune modulation. In the present studies, we show that anandamide caused a concentration-dependent inhibition of interleukin-2 in primary splenocytes. The CB1 and CB2 antagonists, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride] and SR144528 [N-[(1S)-endo-1,3,3,-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], when used in combination, did not antagonize the inhibition of interleukin-2 by anandamide. Additionally, neither UCM707 [N-(3-furanylmethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide], the inhibitor of the putative anandamide membrane transporter (AMT), nor methyl arachidonoyl fluorophosphonate (MAFP), the inhibitor of fatty acid amidohydrolase (FAAH), were able to affect the inhibitory activity of anandamide upon interleukin-2. Interestingly, arachidonic acid caused a concentration-dependent inhibition of interleukin-2 secretion (IC(50) = 10.3 microM), which was similar to that of structurally related anandamide (IC(50) = 11.4 microM). The inhibition of interleukin-2 by anandamide and arachidonic acid was partially reversed by pretreatment with the nonspecific cyclooxygenase inhibitors, flurbiprofen and piroxicam. Moreover, NS398 [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide], a cyclooxygenase-2-specific inhibitor, also attenuated the inhibitory effects of anandamide and arachidonic acid upon interleukin-2 secretion. Finally, pretreatment with a peroxisome proliferator-activated receptor gamma (PPARgamma)-specific antagonist, T0070907 [2-chloro-5-nitro-N-4-pyridinyl-benzamide], partially antagonized anandamide-mediated suppression of IL-2 secretion. Collectively, the aforementioned studies suggest that inhibition of interleukin-2 secretion by anandamide is independent of CB1/CB2 and the AMT/FAAH system. Additionally, these studies also suggest that inhibition of interleukin-2 is mediated by a PPARgamma, which is activated by a cyclooxygenase-2 metabolite of anandamide.
Cheryl E Rockwell; Norbert E Kaminski
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-07-29
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  311     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-15     Completed Date:  2005-01-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  683-90     Citation Subset:  IM    
Department of Pharmacology and Toxicology, B440 Life Sciences Building, Michigan State University, East Lansing, MI 48824, USA.
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MeSH Terms
Amidohydrolases / antagonists & inhibitors
Arachidonic Acid / pharmacology*
Arachidonic Acids / metabolism,  pharmacology*
Benzamides / pharmacology
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / pharmacology
Dose-Response Relationship, Drug
Drug Interactions
Flurbiprofen / pharmacology
Interleukin-2 / secretion*
Isoenzymes / antagonists & inhibitors,  metabolism*
Nitrobenzenes / pharmacology
PPAR gamma / antagonists & inhibitors
Piroxicam / pharmacology
Polyunsaturated Alkamides
Prostaglandin-Endoperoxide Synthases / metabolism*
Pyridines / pharmacology
Receptor, Cannabinoid, CB1 / antagonists & inhibitors
Receptor, Cannabinoid, CB2 / antagonists & inhibitors
Sulfonamides / pharmacology
Grant Support
Reg. No./Substance:
0/Arachidonic Acids; 0/Benzamides; 0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Interleukin-2; 0/Isoenzymes; 0/Nitrobenzenes; 0/PPAR gamma; 0/Polyunsaturated Alkamides; 0/Pyridines; 0/Receptor, Cannabinoid, CB1; 0/Receptor, Cannabinoid, CB2; 0/Sulfonamides; 0/T 0070907; 123653-11-2/N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 36322-90-4/Piroxicam; 506-32-1/Arachidonic Acid; 5104-49-4/Flurbiprofen; 94421-68-8/anandamide; EC 2; EC Synthases; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase

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