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

Nature Chemical Biology volume 6, pages 433441 (2010) | Download Citation

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-γ (PPARγ) 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.

  • Compound C22H32O2

    (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid

  • Compound C22H34O2

    (7Z,10Z,13Z,16Z,19Z)-Docosapentaenoic acid

  • Compound C24H36O4S

    (4Z,7Z,10Z,13Z,19Z)-15-(2-Hydroxyethylthio)-17-oxodocosapentaenoic acid

  • Compound C24H38O4S

    (7Z,10Z,13Z,19Z)-15-(2-Hydroxyethylthio)-17-oxodocosatetraenoic acid

  • Compound C22H34O3

    (7Z,10Z,14E,16Z,19Z)-13-Hydroxydocosapentaenoic acid

  • Compound C22H32O3

    (7Z,10Z,14E,16Z,19Z)-13-Oxodocosapentaenoic acid

  • Compound C22H32O3

    (7Z,10Z,13Z,15E,19Z)-17-Oxodocosapentaenoic acid

  • Compound C22H30O3

    (4Z,7Z,10Z,13Z,15E,19Z)-17-Oxodocosahexaenoic acid

  • Compound C32H49N3O9S

    (7Z,10Z,13Z,19Z)-15-((R)-2-((S)-4-Amino-4-carboxybutanamido)-3-(carboxymethylamino)-3-oxopropylthio)-17-oxodocosatetraenoic acid

  • Compound C32H47N3O9S

    (4Z,7Z,10Z,13Z,19Z)-15-((R)-2-((S)-4-Amino-4-carboxybutanamido)-3-(carboxymethylamino)-3-oxopropylthio)-17-oxodocosapentaenoic acid

  • Compound C22H32O3

    (4Z,7Z,10Z,14E,16Z,19Z)-13-Hydroxydocosahexaenoic acid

  • Compound C22H32O3

    (4Z,7Z,10Z,13Z,15E,19Z)-17-Hydroxydocosahexaenoic acid

  • Compound C22H34O3

    (7Z,10Z,13Z,15E,19Z)-17-Hydroxydocosapentaenoic acid

  • Compound C24H38O4S

    (7Z,10Z,16Z,19Z)-15-(2-Hydroxyethylthio)-13-oxodocosatetraenoic acid

  • Compound C32H49N3O9S

    (7Z,10Z,16Z,19Z)-15-((R)-2-((S)-4-Amino-4-carboxybutanamido)-3-(carboxymethylamino)-3-oxopropylthio)-13-oxodocosatetraenoic acid

  • Compound C22H30O3

    (4Z,7Z,10Z,14E,16Z,19Z)-13-Oxodocosahexaenoic acid

  • Compound C32H47N3O9S

    (4Z,7Z,10Z,16Z,19Z)-15-((R)-2-((S)-4-Amino-4-carboxybutanamido)-3-(carboxymethylamino)-3-oxopropylthio)-13-oxodocosapentaenoic acid

  • Compound C24H36O4S

    (4Z,7Z,10Z,16Z,19Z)-15-(2-Hydroxyethylthio)-13-oxodocosapentaenoic acid

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Acknowledgements

This work was supported by National Institutes of Health grants HL58115 and HL64937, the American Diabetes Association (F.J.S.), and Fondazione Ri.MED, Italy (C.C.). We thank J. Ruzicka and A. Hilderbrand at Thermo Fisher Scientific for assistance with accurate mass measurements of EFOX using an LTQ OrbitrapVelos instrument.

Author information

Author notes

    • Alison L Groeger
    •  & Chiara Cipollina

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Alison L Groeger
    • , Chiara Cipollina
    • , Marsha P Cole
    • , Steven R Woodcock
    • , Gustavo Bonacci
    • , Bruce A Freeman
    •  & Francisco J Schopfer
  2. Fondazione Ri.MED, Piazza Sett'Angeli 10, Palermo, Italy.

    • Chiara Cipollina
  3. Cardiovascular Research Center, University Heart Center Hamburg, Hamburg, Germany.

    • Tanja K Rudolph
    •  & Volker Rudolph

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Contributions

A.L.G., C.C., B.A.F. and F.J.S. designed experiments and prepared the manuscript. A.L.G. performed the search, discovery, and characterization of EFOX and PPARγ-reporter experiments. C.C. performed in vitro COX-2-based synthesis of EFOX, COX-2 siRNA and cell signaling experiments. G.B. performed proteomic analysis. M.P.C., T.K.R. and V.R. assisted with or performed animal-based studies. S.R.W. assisted with chemical derivatization reactions for EFOX characterization.

Competing interests

B.A.F. acknowledges financial interest in Complexa, Inc.

Corresponding authors

Correspondence to Bruce A Freeman or Francisco J Schopfer.

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DOI

https://doi.org/10.1038/nchembio.367

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