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

Abstract

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.

Time-dependent effect of in vivo inflammation on eicosanoid and endocannabinoid levels in plasma, liver, ileum and adipose tissue in C57BL/6 mice fed a fish-oil diet

“…Interestingly, the latter study also showed that AEA and 2-AG levels correlated with markers of inflammation and tissue damage, and that targeting CB2 receptors resulted in decreased inflammatory responses after reperfusion stress. Considering the anti-inflammatory properties of DHEA and EPEA [15,16] and binding to CB2 [40], their levels might also be involved in limiting hepatic tissue damage during inflammatory or reperfusion stress.…”

“…Antiinflammatory properties have been described for the n-3 fatty acid derived NAEs docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) (see Fig. 1), and these compounds were more potent than AEA in inhibiting nitric oxide release from macrophages [15,16]. Increased levels of NAEs during inflammation have been described in several in vitro and animals models [17][18][19], and are observed in parallel with decreased expression of the primary NAE degrading enzyme fatty acid amide hydrolase (FAAH) [18].…”

Docosahexaenoic acid attenuates in endocannabinoid synthesis in RAW 264.7 macrophages activated with benzo(a)pyrene and lipopolysaccharide

“…The presence of the endocannabinoids from DHA and nervonic acid, and the effects on immune cells have to date been poorly studied. Meijerink et al (2011) demonstrated that EPEA and DHEA both attenuate lipopolysaccharide-induced nitric oxide production in a macrophage cell line. Some studies showed that DHEA has antiinflammatory properties in macrophages which are at least partly mediated through an interaction with the CB2 receptor (Balvers et al, 2010;Kim and Watkins, 2014).…”

“…Mechanisms to curtail the inflammatory response and promote its resolution are of immense interest (Clària et al, 2011;Meijerink et al, 2011;Serhan and Petasis, 2011;Davidson et al, 2012;Wahli and Michalik, 2012;Fritsche, 2015). A number of studies have appreciated that low-grade inflammation can be described as a long-term inflammatory response triggered by nutrients and metabolic surplus (Clària et al, 2011;Fritsche, 2015).…”

Omega-3 DHA- and EPA–dopamine conjugates induce PPARγ-dependent breast cancer cell death through autophagy and apoptosis

“…Moreover, it has been demonstrated that some of these molecules show affinity for different receptors, including cannabinoid receptors (CB 1 and Particularly, it has been reported that the n-3 acyl-ethanolamines, DHEA and EPEA, show antiinflammatory or general immune modulating properties [18,19] and possess anti-tumoral activities in prostate cancer cells [20]. We have recently found that DHEA and EPEA induce autophagy through PPAR activation in human breast cancer cells [21], highlighting the importance of these compounds from a pharmacological perspective.…”