Cyclooxygenase-2 Generates Anti-inflammatory Mediators from Omega-3 Fatty Acids

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2010 May 4

PMID 20436486

Citations 127

Authors

Alison L Groeger

Chiara Cipollina

Marsha P Cole

Steven R Woodcock

Gustavo Bonacci

Tanja K Rudolph

Volker Rudolph

Bruce A Freeman

Francisco J Schopfer

Affiliations

Soon will be listed here.

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.

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References

Alvarez M, Trujillo M, Radi R . Peroxynitrite formation from biochemical and cellular fluxes of nitric oxide and superoxide. Methods Enzymol. 2002; 359:353-66. DOI: 10.1016/s0076-6879(02)59198-9. View

Connor W . Importance of n-3 fatty acids in health and disease. Am J Clin Nutr. 2000; 71(1 Suppl):171S-5S. DOI: 10.1093/ajcn/71.1.171S. View

Levonen A, Landar A, Ramachandran A, Ceaser E, Dickinson D, Zanoni G . Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J. 2003; 378(Pt 2):373-82. PMC: 1223973. DOI: 10.1042/BJ20031049. View

Fedor D, Kelley D . Prevention of insulin resistance by n-3 polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care. 2009; 12(2):138-46. DOI: 10.1097/MCO.0b013e3283218299. View

Wei C, Zhu P, Shah S, Blair I . 15-oxo-Eicosatetraenoic acid, a metabolite of macrophage 15-hydroxyprostaglandin dehydrogenase that inhibits endothelial cell proliferation. Mol Pharmacol. 2009; 76(3):516-25. PMC: 2730384. DOI: 10.1124/mol.109.057489. View

Malur A, McCoy A, Arce S, Barna B, Kavuru M, Malur A . Deletion of PPAR gamma in alveolar macrophages is associated with a Th-1 pulmonary inflammatory response. J Immunol. 2009; 182(9):5816-22. DOI: 10.4049/jimmunol.0803504. View

Stark K, Wongsud B, Burman R, Oliw E . Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8. Arch Biochem Biophys. 2005; 441(2):174-81. DOI: 10.1016/j.abb.2005.07.003. View

Cui T, Schopfer F, Zhang J, Chen K, Ichikawa T, Baker P . Nitrated fatty acids: Endogenous anti-inflammatory signaling mediators. J Biol Chem. 2006; 281(47):35686-98. PMC: 2169500. DOI: 10.1074/jbc.M603357200. View

Musiek E, Brooks J, Joo M, Brunoldi E, Porta A, Zanoni G . Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J Biol Chem. 2008; 283(29):19927-35. PMC: 2459280. DOI: 10.1074/jbc.M803625200. View

10.

Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S . Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005; 201(5):713-22. PMC: 2212834. DOI: 10.1084/jem.20042031. View

11.

Mochizuki M, Ishii Y, Itoh K, Iizuka T, Morishima Y, Kimura T . Role of 15-deoxy delta(12,14) prostaglandin J2 and Nrf2 pathways in protection against acute lung injury. Am J Respir Crit Care Med. 2005; 171(11):1260-6. DOI: 10.1164/rccm.200406-755OC. View

12.

Kim E, Surh Y . 15-deoxy-Delta12,14-prostaglandin J2 as a potential endogenous regulator of redox-sensitive transcription factors. Biochem Pharmacol. 2006; 72(11):1516-28. DOI: 10.1016/j.bcp.2006.07.030. View

13.

Schopfer F, Batthyany C, Baker P, Bonacci G, Cole M, Rudolph V . Detection and quantification of protein adduction by electrophilic fatty acids: mitochondrial generation of fatty acid nitroalkene derivatives. Free Radic Biol Med. 2009; 46(9):1250-9. PMC: 3144282. DOI: 10.1016/j.freeradbiomed.2008.12.025. View

14.

Lavie C, Milani R, Mehra M, Ventura H . Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol. 2009; 54(7):585-94. DOI: 10.1016/j.jacc.2009.02.084. View

15.

Waku T, Shiraki T, Oyama T, Morikawa K . Atomic structure of mutant PPARgamma LBD complexed with 15d-PGJ2: novel modulation mechanism of PPARgamma/RXRalpha function by covalently bound ligands. FEBS Lett. 2008; 583(2):320-4. DOI: 10.1016/j.febslet.2008.12.017. View

16.

BLIGH E, Dyer W . A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959; 37(8):911-7. DOI: 10.1139/o59-099. View

17.

Arita M, Oh S, Chonan T, Hong S, Elangovan S, Sun Y . Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J Biol Chem. 2006; 281(32):22847-54. DOI: 10.1074/jbc.M603766200. View

18.

Haridas V, Higuchi M, Jayatilake G, Bailey D, Mujoo K, Blake M . Avicins: triterpenoid saponins from Acacia victoriae (Bentham) induce apoptosis by mitochondrial perturbation. Proc Natl Acad Sci U S A. 2001; 98(10):5821-6. PMC: 33297. DOI: 10.1073/pnas.101619098. View

19.

Erlemann K, Cossette C, Grant G, Lee G, Patel P, Rokach J . Regulation of 5-hydroxyeicosanoid dehydrogenase activity in monocytic cells. Biochem J. 2006; 403(1):157-65. PMC: 1828885. DOI: 10.1042/BJ20061617. View

20.

Thornalley P . Isothiocyanates: mechanism of cancer chemopreventive action. Anticancer Drugs. 2002; 13(4):331-8. DOI: 10.1097/00001813-200204000-00001. View