Abstract
Docosahexaenoyl ethanolamide (DHEA), the ethanolamine conjugate of the n-3 long chain polyunsaturated fatty acid docosahexaenoic acid, is endogenously present in the human circulation and in tissues. Its immunomodulating properties have been (partly) attributed to an interaction with the cyclooxygenase-2 (COX-2) enzyme. Recently, we discovered that COX-2 converts DHEA into two oxygenated metabolites, 13- and 16-hydroxylated-DHEA (13- and 16-HDHEA, respectively). It remained unclear whether these oxygenated metabolites also display immunomodulating properties like their parent DHEA. In the current study we investigated the immunomodulating properties of 13- and 16-HDHEA in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compounds reduced production of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β and IL-1Ra, but did not affect nitric oxide (NO) and IL-6 release. Transcriptome analysis showed that the compounds inhibited the LPS-mediated induction of pro-inflammatory genes (InhbA, Ifit1) and suggested potential inhibition of regulators such as toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 3 (IRF3), whereas anti-inflammatory genes (SerpinB2) and potential regulators IL-10, sirtuin 1 (Sirt-1), fluticasone propionate were induced. Additionally, transcriptome analysis of 13-HDHEA suggests a potential anti-angiogenic role. In contrast to the known oxylipin-lowering effects of DHEA, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses revealed that 13- and 16-HDHEA did not affect oxylipin formation. Overall, the anti-inflammatory effects of 13-HDHEA and 16-HDHEA are less pronounced compared to their parent molecule DHEA. Therefore, we propose that COX-2 metabolism of DHEA acts as a regulatory mechanism to limit the anti-inflammatory properties of DHEA.
Highlights
Long chain n-3 polyunsaturated fatty acids (LC-PUFAs) are essential for neural development and functioning, and have been linked to certain beneficial health effects
docosahexaenoyl ethanolamide (DHEA) is endogenously present in the circulation and tissues in humans and animals [15,20,21,22,23,24,25], and its levels are generally increased after docosahexaenoic acid (DHA) intake, for example by consumption of n-3 fatty acid-containing products such as fatty fish or fish oil supple ments [15,20,22,26]
We demonstrated that purified COX-2 converts DHEA into 13- and 16-HDHEA, and we confirmed its formation in 1.0 μg/mL LPS-stimulated RAW264.7 macrophages (Fig. 1) [38]
Summary
Long chain n-3 polyunsaturated fatty acids (LC-PUFAs) are essential for neural development and functioning, and have been linked to certain beneficial health effects. The potential health effects of n-3 LCPUFAs are continuously being challenged by new studies. Suggested explanations for these apparent discrepancies are differences in the level of intake or administered dose, and the study population [1]. Increased dietary DHA intake alters the cell membrane composition leading to a higher n-3 content This change in membrane composition leads to a decreased production of pro-inflammatory n-6 oxylipins and increases the pro duction of potent inflammation resolving n-3 oxylipins including resolvins, protectins, and maresins [1,11,15,16,17,18,19]. DHEA inhibits neuroinflammation via interac tion with the GPR110 [28,30], and reduces the production of inflam mation markers like monocyte chemoattractant protein 1 (MCP-1), NO, IL-6, and prostaglandin E2 (PGE2) in LPS-stimulated RAW264.7 mac rophages and 3T3-L1 adipocytes [1,29,31,32,33]
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