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Augmentation of endogenous cannabinoid tone modulates lipopolysaccharide‐induced alterations in circulating cytokine levels in rats
Author(s) -
Roche Michelle,
Kelly John P.,
O’Driscoll Maeve,
Finn David P.
Publication year - 2008
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2008.02838.x
Subject(s) - am251 , anandamide , fatty acid amide hydrolase , endocannabinoid system , trpv1 , cannabinoid receptor , cannabinoid , chemistry , endocrinology , pharmacology , medicine , receptor antagonist , cytokine , receptor , antagonist , biology , transient receptor potential channel
Summary 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‐α (TNF‐α) levels. The peroxisome proliferator‐activated receptor γ (PPARγ) antagonist, GW9662, attenuated the AM404‐induced augmentation of TNF‐α levels. Furthermore, the selective cannabinoid CB 1 and CB 2 receptor antagonists, AM251 and AM630 respectively, and the transient receptor potential vanilloid receptor‐1 (TRPV1) antagonist, SB366791, reduced LPS‐induced TNF‐α plasma levels both alone and in combination with AM404. In contrast, AM404 inhibited LPS‐induced increases in circulating interleukin‐1β (IL‐1β) and IL‐6. AM251 attenuated the immunosuppressive effect of AM404 on IL‐1β. 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‐1β and IL‐6 levels. In conclusion, inhibition of endocannabinoid degradation or transport in vivo potentiates LPS‐induced increases in circulating TNF‐α levels, an effect which may be mediated by PPARγ and is also reduced by pharmacological blockade of CB 1 , CB 2 and TRPV1. The immunosuppressive effect of AM404 on IL‐1β levels is mediated by the cannabinoid CB 1 receptor. Improved understanding of endocannabinoid‐mediated regulation of immune function has fundamental physiological and potential therapeutic significance.