Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids

Nat Chem Biol. 2010 Jun;6(6):433-41. doi: 10.1038/nchembio.367. Epub 2010 May 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology
  • Borohydrides / pharmacology
  • Cell Line
  • Cell Membrane / metabolism
  • Cyclooxygenase 2 / metabolism*
  • Docosahexaenoic Acids / chemistry
  • Docosahexaenoic Acids / metabolism
  • Fatty Acids, Omega-3 / metabolism*
  • Fatty Acids, Unsaturated / metabolism
  • Fatty Acids, Unsaturated / pharmacology
  • Glutathione / metabolism
  • Humans
  • Hydroxylation
  • Interleukin-10 / genetics
  • Interleukin-6 / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • PPAR gamma / metabolism
  • PPAR gamma / pharmacology


  • Anti-Inflammatory Agents
  • Borohydrides
  • Fatty Acids, Omega-3
  • Fatty Acids, Unsaturated
  • Interleukin-6
  • PPAR gamma
  • Interleukin-10
  • Docosahexaenoic Acids
  • sodium borohydride
  • Cyclooxygenase 2
  • Glutathione