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Omega-3 fatty acid-derived oxylipins reduce inflammation response in human macrophages: putative mechanism through PPAR-gamma binding
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The anti-inflammatory properties of omega 3 fatty acids have been largely demonstrated in vitro and in vivo but research gaps remain regarding the contribution of their oxygenated metabolites also called oxylipins. We aimed to investigate and compare the anti-inflammatory properties and potential mechanisms of action of different types of omega 3 fatty acid-derived oxylipins including (i) four DHA-derived oxylipins, i.e. Neuroprostanes (14-A4- and 4(RS)-4-F4t-NeuroP), Protectin DX (PDX) as well as Neuroprotectin D1 (NPD1/PD1), (ii) a n-3 DPA derived oxylipin i.e. 10S,17S-diH n-3 DPAEEZ, (iii) two phytoprostanes (16-B1-PhytoP and 9-L1-PhytoP) and their enantiomers and one phytofuran (ent-16-(RS)-epi-9-PhytoF).Human peripheral blood mononuclear cells were isolated from healthy donors by Ficoll density gradient centrifugation. Monocytes were differentiated into resting macrophages (RM) for 7 days. RM were exposed to the different types of oxylipins at 3 different doses (i.e. 0.1, 1 and 10 μM) during 30 min. The inflammatory response was then induced with LPS (100 ng/mL) for 6 hours.Preliminary results of gene expression analysis (qPCR) show that IL-6, MCP-1, COX-2, TNF-alpha or CCL3 mRNA were significantly lower in macrophages pre-exposed to 10μM 14-A4-NeuroP (-84%, -57%, -29%, -41% and -23% respectively). Significant but less pronounced effects on IL-6 and MCP-1 were also observed with 10μM 4(RS)-4-F4t-NeuroP (-25% and -25% respectively). Reduced levels of TNF-alpha protein secretion (ELISA) were found in macrophages pre-exposed to 10μM 4(RS)-4-F4t-NeuroP (-12% p<0.05) while measurable but less pronounced effects were observed with 14-A4-NeuroP, PDX, PD1 or 10S,17S-diH n-3 DPAEEZ (-9%, -22%, -10% and -15% ns, respectively). Abundance and phosphorylation of IκB-alpha (Western Blot) suggest that 14-A4- and 4(RS)-4-F4t-NeuroPs could exert their anti-inflammatory effects through the inhibition of IκB-alpha phosphorylation. Finally, cotransfection of luciferase reporter vector with human PPAR-gamma expression vector performed in Cos-7 cells suggests that all tested oxylipins may act in part through PPAR-gamma.In conclusion, these results suggest that the anti-inflammatory properties of omega 3 fatty acids could be mediated, at least in part, by oxylipins, and bring new insights into their mechanism of action
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