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PMID: 18393970 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Augmentation of endogenous cannabinoid tone modulates lipopolysaccharide-induced alterations in circulating cytokine levels in rats.

Immunology ·Vol. 125 ·No. 2 ·2008-10-00 ·Pages 263-71

Roche M, Kelly JP, O'Driscoll M, Finn DP

Abstract

The endogenous cannabinoid system plays an important role in regulating the immune system. Modulation of endogenous cannabinoids represents an attractive alternative for the treatment of inflammatory disorders. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme catalysing degradation of the endogenous cannabinoid anandamide, and AM404, an inhibitor of anandamide transport, on lipopolysaccharide (LPS)-induced increases in plasma cytokine levels in rats. Both URB597 and AM404 potentiated the LPS-induced increase in plasma tumour necrosis factor-alpha (TNF-alpha) levels. The peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, GW9662, attenuated the AM404-induced augmentation of TNF-alpha levels. Furthermore, the selective cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630 respectively, and the transient receptor potential vanilloid receptor-1 (TRPV1) antagonist, SB366791, reduced LPS-induced TNF-alpha plasma levels both alone and in combination with AM404. In contrast, AM404 inhibited LPS-induced increases in circulating interleukin-1beta (IL-1beta) and IL-6. AM251 attenuated the immunosuppressive effect of AM404 on IL-1beta. None of the antagonists altered the effect of AM404 on LPS-induced IL-6. Moreover, AM251, AM630 and SB366791, administered alone, inhibited LPS-induced increases in plasma IL-1beta and IL-6 levels. In conclusion, inhibition of endocannabinoid degradation or transport in vivo potentiates LPS-induced increases in circulating TNF-alpha levels, an effect which may be mediated by PPARgamma and is also reduced by pharmacological blockade of CB1, CB2 and TRPV1. The immunosuppressive effect of AM404 on IL-1beta levels is mediated by the cannabinoid CB1 receptor. Improved understanding of endocannabinoid-mediated regulation of immune function has fundamental physiological and potential therapeutic significance.

MeSH Terms
Anilides/pharmacology Animals Arachidonic Acids/pharmacology Benzamides/pharmacology Cannabinoid Receptor Modulators/immunology Carbamates/pharmacology Cinnamates/pharmacology Cytokines/biosynthesis Drug Synergism Indoles/pharmacology Interleukin-1beta/blood Interleukin-6/blood Lipopolysaccharides/antagonists & inhibitors,immunology Male Piperidines/pharmacology Pyrazoles/pharmacology Rats Rats, Sprague-Dawley Tumor Necrosis Factor-alpha/biosynthesis
Chemicals
2-chloro-5-nitrobenzanilide Anilides Arachidonic Acids Benzamides Cannabinoid Receptor Modulators Carbamates Cinnamates Cytokines Indoles Interleukin-1beta Interleukin-6 Lipopolysaccharides N-(3-methoxyphenyl)-4-chlorocinnamanilide Piperidines Pyrazoles Tumor Necrosis Factor-alpha cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester AM 251 iodopravadoline N-(4-hydroxyphenyl)arachidonylamide
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Roche Michelle
Department of Pharmacology and Therapeutics, NCBES Neuroscience Cluster and Centre for Pain Research, National University of Ireland, Galway, Ireland. [email protected]
Kelly John P
O'Driscoll Maeve
Finn David P
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Article Info
Journal
Immunology
Abbr.
Immunology
ISSN
1365-2567
DOI
10.1111/j.1365-2567.2008.02838.x
Email
[email protected]
Published
2008-10-00
Epub
2008-00-03
Pages
263-71
Language
English
Region
England
NLM ID
0374672
PMCID
PMC2561133
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1365-2567.2008.02838.x PMC Full Text View journal details
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