Inhibition of COX-2-mediated eicosanoid production plays a major role in the anti-inflammatory effects of the endocannabinoid N-docosahexaenoylethanolamine (DHEA) in macrophages.

 2014 Apr 30. doi: 10.1111/bph.12747. [Epub ahead of print]

pm8

Abstract

BACKGROUND AND PURPOSE:

DHEA (N-docosahexaenoylethanolamine) is the ethanolamine conjugate of the long chain polyunsaturated n-3 fatty acid DHA (docosahexaenoic; 22 : 6n-3). Its concentration in animal tissues and human plasma increases when diets rich in fish or krill oil are consumed. DHEA displays anti-inflammatory properties in vitro and was found to be released during an inflammatory response in mice. Here we further examine possible targets involved in the immune-modulating effects of DHEA.

EXPERIMENTAL APPROACH:

Antagonists for CB1 , CB2 and PPAR were used to explore effects of DHEA on NO release by LPS-stimulated RAW264.7 cells. Possible involvement of CB2 receptors was also studied by comparing effects in LPS-stimulated peritoneal macrophages obtained from CB2 -/- and CB+/+ mice. Effects on NF-κB activation were determined using a reporter cell line. To study DHEA effects on COX-2 and LOX activity, 21 different eicosanoids produced by LPS-stimulated RAW264.7 cells were quantified by LC-MS/MS. Finally, effects on mRNA expression profiles were analysed using gene arrays followed by Ingenuity® Pathways Analysis.

KEY RESULTS:

Effects of DHEA on NO release appeared to be independent from CB1 , CB2 or PPAR receptors. NF-κB and IFNβ, key elements of the MyD88-dependent and MyD88-independent pathways were not decreased. By contrast, DHEA significantly reduced levels of several COX-2 generated eicosanoids. Gene expression analysis provided support for an effect on COX-2-mediated pathways.

CONCLUSIONS AND IMPLICATIONS:

Our findings suggest that anti-inflammatory effects of DHEA in macrophages are predominantly taking place via inhibition of eicosanoids produced through COX-2.

This article is protected by copyright. All rights reserved.

KEYWORDS:

CB2 , COX-2, DHA, DHEA, N-docosahexaenoylethanolamine, PGE2, TLR3, TLR4, docosahexaenoylethanolamide, endocannabinoid, inflammation, n-3 fatty acids, nitric oxide, prostaglandins

PMID:

 

24780080

 

[PubMed – as supplied by publisher]
potp font 1

Tags: , , , , , , , , , , , , ,