Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids.
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.
Groeger
Alison L
AL
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Cipollina
Chiara
C
Cole
Marsha P
MP
Woodcock
Steven R
SR
Bonacci
Gustavo
G
Rudolph
Tanja K
TK
Rudolph
Volker
V
Freeman
Bruce A
BA
Schopfer
Francisco J
FJ
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
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