title: Neuroprostanes, produced by free-radical mediated peroxidation of DHA, inhibit the inflammatory response of human macrophages.
abstract: The anti-inflammatory properties of DHA have been largely demonstrated in vitro and in vivo but research gaps remain regarding the contribution of the oxygenated metabolites. Among them, we are focusing on prostaglandin-like molecules termed Neuroprostanes (NeuroPs) which are produced through free-radical-mediated peroxidation of DHA. We hypothesized that these specific molecules which are highly reactive and produced in abundance during oxidative stress and inflammation could contribute to the anti-inflammatory properties of DHA. Human peripheral blood mononuclear cells were isolated from healthy donors by Ficoll density gradient centrifugation. Monocytes were differentiated into resting macrophages (RM) for 6 days (37°C, 5% CO2). RM were exposed to 2 different types of NeuroPs (i.e. 14-A4-NeuroP and 4-F4t-NeuroP, 10µM) or ethanol (vehicle 0.15%) during 30min. Then LPS (100ng/mL) was added for 6hours to induced inflammatory response. Both types of NeuroPs (14-A4-NeuroP and 4-F4t-NeuroP) significantly decreased the mRNA levels of IL-6 (-49% and -26% respectively) and MCP-1 (-55% and -24% respectively). Secretion of TNFα and MCP-1 was also reduced when RM were exposed to 14-A4-NeuroP (-10%, ns and -34%, p<0.05) and 4-F4t-NeuroP (-12%, p<0.01 and 25%, ns). Preliminary results regarding the expression and phosphorylation of IkBa suggest that 4-F4t-NeuroP could exert its anti-inflammatory effects through the inhibition of IkBa phosphorylation. Finally, cotransfection of luciferase reporter vector with hPPARg expression vector performed on Cos-7 cells suggests that NeuroPs probably act independently of PPARg. In conclusion, these results suggest that the anti-inflammatory properties of DHA could be mediated, at least in part, by NeuroPs which corroborates the importance of oxidative stress in cell signaling.
authors.affiliation: INRA (Human Nutrition), Centre de Theix, France. Electronic address: cecile.gladine@clermont.inra.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gladine
authors.affiliation: INRA (Human Nutrition), Centre de Theix, France.
authors.forename: Joumard-Cubizolles
authors.initials: JC
authors.lastname: Laurie
authors.affiliation: INSERM (Institut Pasteur), Lille, France.
authors.forename: Chinetti
authors.initials: C
authors.lastname: Giulia
authors.affiliation: INRA (Human Nutrition), Centre de Theix, France.
authors.forename: Bayle
authors.initials: B
authors.lastname: Dominique
authors.affiliation: INSERM (Institut Pasteur), Lille, France.
authors.forename: Copin
authors.initials: C
authors.lastname: Corinne
authors.affiliation: INSERM (Institut Pasteur), Lille, France.
authors.forename: Hennuyer
authors.initials: H
authors.lastname: Nathalie
authors.affiliation: INSERM (Institut Pasteur), Lille, France.
authors.forename: Staels
authors.initials: S
authors.lastname: Bart
authors.affiliation: Université de Pavie (Université de Pavie), Université de Pavie, Italie.
authors.forename: Zanoni
authors.initials: Z
authors.lastname: Giuseppe
authors.affiliation: Université de Pavie (Université de Pavie), Université de Pavie, Italie.
authors.forename: Porta
authors.initials: P
authors.lastname: Alessio
authors.affiliation: CNRS (IBMM), IBMM, France.
authors.forename: Galano
authors.initials: G
authors.lastname: Jean-Marie
authors.affiliation: CNRS (IBMM), IBMM, France.
authors.forename: Oger
authors.initials: O
authors.lastname: Camille
authors.affiliation: CNRS (IBMM), IBMM, France.
authors.forename: Durand
authors.initials: D
authors.lastname: Thierry