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

Abstract：

BACKGROUND AND PURPOSE:N-docosahexaenoylethanolamine (DHEA) is the ethanolamine conjugate of the long-chain polyunsaturated n-3 fatty acid docosahexaenoic (DHA; 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 cannabinoid (CB)1 and CB2 receptors and PPARγ were used to explore effects of DHEA on NO release by LPS-stimulated RAW264.7 cells. The possible involvement of CB2 receptors was studied by comparing effects in LPS-stimulated peritoneal macrophages obtained from CB2 (-/-) and CB2 (+/+) mice. Effects on NF-κB activation were determined using a reporter cell line. To study DHEA effects on COX-2 and lipoxygenase 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:CB1 and CB2 receptors or PPARs were not involved in the effects of DHEA on NO release. NF-κB and IFN-β, key elements of the myeloid differentiation primary response protein D88 (MyD88)-dependent and MyD88-independent pathways were not decreased. By contrast, DHEA significantly reduced levels of several COX-2-derived eicosanoids. Gene expression analysis provided support for an effect on COX-2-mediated pathways. CONCLUSIONS AND IMPLICATIONS:Our findings suggest that the anti-inflammatory effects of DHEA in macrophages predominantly take place via inhibition of eicosanoids produced through COX-2. LINKED ARTICLES:This article is part of a themed section on Cannabinoids 2013 published in volume 171 issue 6. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2014.171.issue-6/issuetoc.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Meijerink J,Poland M,Balvers MG,Plastina P,Lute C,Dwarkasing J,van Norren K,Witkamp RF

doi

10.1111/bph.12747

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

24-37

issue

eissn

0007-1188

issn

1476-5381

journal_volume

172

pub_type

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