British Journal of Nutrition

Nutritional Immunology

The ethanolamide metabolite of DHA, docosahexaenoylethanolamine, shows immunomodulating effects in mouse peritoneal and RAW264.7 macrophages: evidence for a new link between fish oil and inflammation

Jocelijn Meijerinka1 c1, Pierluigi Plastinaa1, Jean-Paul Vinckena2, Mieke Polanda1, Mohamed Attyaa1, Michiel Balversa1a3, Harry Gruppena2, Bartolo Gabrielea4 and Renger F. Witkampa1a3

a1 Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV, Wageningen, The Netherlands

a2 Laboratory of Food Chemistry, Wageningen University, PO Box 8129, 6700 EV, Wageningen, The Netherlands

a3 TNO Quality of Life, PO Box 360, 3700 AJ Zeist, The Netherlands

a4 Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036, Arcavacata di Rende, Cosenza, Italy


Several mechanisms have been proposed for the positive health effects associated with dietary consumption of long-chain n-3 PUFA (n-3 LC-PUFA) including DHA (22 : 6n-3) and EPA (20 : 5n-3). After dietary intake, LC-PUFA are incorporated into membranes and can be converted to their corresponding N-acylethanolamines (NAE). However, little is known on the biological role of these metabolites. In the present study, we tested a series of unsaturated NAE on the lipopolysaccharide (LPS)-induced NO production in RAW264.7 macrophages. Among the compounds tested, docosahexaenoylethanolamine (DHEA), the ethanolamide of DHA, was found to be the most potent inhibitor, inducing a dose-dependent inhibition of NO release. Immune-modulating properties of DHEA were further studied in the same cell line, demonstrating that DHEA significantly suppressed the production of monocyte chemotactic protein-1 (MCP-1), a cytokine playing a pivotal role in chronic inflammation. In LPS-stimulated mouse peritoneal macrophages, DHEA also reduced MCP-1 and NO production. Furthermore, inhibition was also found to take place at a transcriptional level, as gene expression of MCP-1 and inducible NO synthase was inhibited by DHEA. To summarise, in the present study, we showed that DHEA, a DHA-derived NAE metabolite, modulates inflammation by reducing MCP-1 and NO production and expression. These results provide new leads in molecular mechanisms by which DHA can modulate inflammatory processes.

(Received July 30 2010)

(Revised November 18 2010)

(Accepted December 03 2010)

(Online publication February 04 2011)


c1 Corresponding author: J. Meijerink, fax +31 317 483342, email


Abbreviations: AEA, arachidonoylethanolamine; BCA, bicinchoninic acid; DEA, docosatetraenoylethanolamine; DHEA, docosahexaenoylethanolamine; EPEA, eicosapentaenoylethanolamine; iNOS, inducible NO synthase; LPS, lipopolysaccharide; MCP-1, monocyte chemotactic protein-1; n-3 LC-PUFA, n-3 long-chain PUFA; NAE, N-acylethanolamine; RPMI-1640, Roswell Park Memorial Institute 1640; ZTT, tetrazolium salt