title: Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid.
abstract: The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) possesses potent anti-inflammatory properties and has shown therapeutic benefit in numerous inflammatory diseases. However, the molecular mechanisms of these anti-inflammatory properties are poorly understood. DHA is highly susceptible to peroxidation, which yields an array of potentially bioactive lipid species. One class of compounds are cyclopentenone neuroprostanes (A(4)/J(4)-NPs), which are highly reactive and similar in structure to anti-inflammatory cyclopentenone prostaglandins. Here we show that a synthetic A(4)/J(4)-NP, 14-A(4)-NP (A(4)-NP), potently suppresses lipopolysaccharideinduced expression of inducible nitric-oxide synthase and cyclooxygenase-2 in macrophages. Furthermore, A(4)-NP blocks lipopolysaccharide-induced NF-kappaB activation via inhibition of Ikappa kinase-mediated phosphorylation of IkappaBalpha. Mutation on Ikappa kinase beta cysteine 179 markedly diminishes the effect of A(4)-NP, suggesting that A(4)-NP acts via thiol modification at this residue. Accordingly, the effects of A(4)-NP are independent of peroxisome proliferator-activated receptor-gamma and are dependent on an intact reactive cyclopentenone ring. Interestingly, free radical-mediated oxidation of DHA greatly enhances its anti-inflammatory potency, an effect that closely parallels the formation of A(4)/J(4)-NPs. Furthermore, chemical reduction or conjugation to glutathione, both of which eliminate the bioactivity of A(4)-NP, also abrogate the anti-inflammatory effects of oxidized DHA. Thus, we have demonstrated that A(4)/J(4)-NPs, formed via the oxidation of DHA, are potent inhibitors of NF-kappaB signaling and may contribute to the anti-inflammatory actions of DHA. These findings have implications for understanding the anti-inflammatory properties of omega-3 fatty acids, and elucidate novel interactions between lipid peroxidation products and inflammation.
authors.affiliation: Division of Clinical Pharmacology, and Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Musiek
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Brooks
authors.forename: Myungsoo
authors.initials: M
authors.lastname: Joo
authors.forename: Enrico
authors.initials: E
authors.lastname: Brunoldi
authors.forename: Alessio
authors.initials: A
authors.lastname: Porta
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vidari
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: BethAnn
authors.initials: B
authors.lastname: McLaughlin
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003517:Cyclopentanes / Q000737:chemistry* / Q000494:pharmacology*; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism*; D004583:Electrons; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D003517:Cyclopentanes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D004281:Docosahexaenoic Acids; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; C013905:cyclopentenone