title: Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids.
abstract: Electrophilic fatty acids are generated during inflammation by non-enzymatic reactions and can modulate inflammatory responses. We used a new mass spectrometry-based electrophile capture strategy to reveal the formation of electrophilic oxo-derivatives (EFOX) from the omega-3 fatty acids docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). These EFOX were generated by a cyclooxygenase-2 (COX-2)-catalyzed mechanism in activated macrophages. Modulation of COX-2 activity by aspirin increased the rate of EFOX production and their intracellular levels. Owing to their electrophilic nature, EFOX adducted to cysteine and histidine residues of proteins and activated Nrf2-dependent anti-oxidant gene expression. We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin.
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Groeger
authors.forename: Chiara
authors.initials: C
authors.lastname: Cipollina
authors.forename: Marsha P
authors.initials: MP
authors.lastname: Cole
authors.forename: Steven R
authors.initials: SR
authors.lastname: Woodcock
authors.forename: Gustavo
authors.initials: G
authors.lastname: Bonacci
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Rudolph
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Schopfer
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001894:Borohydrides / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D001894:Borohydrides; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D015850:Interleukin-6; D047495:PPAR gamma; D016753:Interleukin-10; D004281:Docosahexaenoic Acids; C025364:sodium borohydride; D051546:Cyclooxygenase 2; D005978:Glutathione