Contrasting Effects of n-3 and n-6 Fatty Acids on Cyclooxygenase-2 in Model Systems for Arthritis

Abstract

Cyclooxygenase-2 (COX-2) is intimately involved in symptoms of arthritis while dietary n-3 polyunsaturated fatty acids (PUFA) are thought to be beneficial. In these experiments, using both bovine and human in vitro systems that mimic features of arthritis, we show that the n-3 PUFA eicosapentaenoic acid (EPA) is able to reduce mRNA and protein levels of COX-2. Activity, as assessed through prostaglandin E2 formation, was also reduced in a dose-dependent manner. These effects of EPA contrasted noticeably with the n-6 PUFA, arachidonic acid. The data provide direct evidence for a molecular mechanism by which dietary n-3 PUFA, such as EPA, can reduce inflammation and, hence, associated symptoms in arthritis.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

ARA:

Arachidonic acid

BCIP:

5-bromo-4-chlorindolyl phosphate

COX:

Cyclooxygenase

DHA:

All cis-Δ4, 7, 10, 13, 16, 19-docosahexaenoic acid

DMEM:

Dulbecco’s modified Eagle’s medium

EPA:

All cis-Δ5, 8, 11, 14, 17-eicosapentaenoic acid

FCS:

Foetal calf serum

FGF:

Fibroblast growth factor

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

IL-1:

Interleukin-1

NBT:

Nitroblue tetrazolium

NSAIDs:

Non-steroidal anti-inflammatory drugs

OA:

Osteoarthritis

PDGF:

Platelet-derived growth factor

PG:

Prostaglandin

PUFA:

Polyunsaturated fatty acid

RA:

Rheumatoid arthritis

TNF-α:

Tumour necrosis factor-α

TSA:

TRIZMA saline azide

References

  1. 1.

    Gunstone FD, Harwood JL, Dijkstra AJ (eds) (2006) The lipid handbook, 3rd edn. Taylor and Francis, Boca Raton

    Google Scholar 

  2. 2.

    Simopoulos AP (2006) Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 60:502–507

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Serhan CN, Makato A, Hong S, Gotlinger K (2004) Resolvins, docosatrienes and neuroprotectins, novel omega-3-derived mediators and their endogenous aspirin-triggered epimers. Lipids 39:1125–1132

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    MacLean CH, Mojica WA, Morton SC, Pencharz J, Hasenfeld R et al (2004) Effects of omega-3 fatty acids on lipids and glycemic control in Type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus and osteoporosis. Summary, Evidence Report/Technology Assessment no. 89. AHRQ Publication no. 04-E012-1. Rockville

  5. 5.

    Lands WEM (2005) Fish, omega-3 and human health, 2nd edn. American Oil Chemists Society, Champaign

    Google Scholar 

  6. 6.

    Cunnane SC (2003) Problems with essential fatty acids: time for a new paradigm? Prog Lipid Res 42:544–568

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Harwood JL, Caterson B (2006) Dietary omega-3 polyunsaturated fatty acids and inflammation. Lipid Technol 18:7–10

    CAS  Google Scholar 

  8. 8.

    von Schacky C, Harris WS (2007) Cardiovascular benefit of omega-3 fatty acids. Cardiovasc Res 73:310–315

    Article  Google Scholar 

  9. 9.

    Morris MC, Evans DA, Bienias JC, Tangney CC, Bennett DA et al (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer’s disease. Arch Neurol 60:940–946

    Article  PubMed  Google Scholar 

  10. 10.

    Rayman M, Callaghan A (2006) Nutrition and arthritis. Blackwell, Oxford

    Book  Google Scholar 

  11. 11.

    Calder PC, Zurier RB (2001) Polyunsaturated fatty acids and rheumatoid arthritis. Cur Opin Clin Nutr Metab Care 4:115–121

    Article  CAS  Google Scholar 

  12. 12.

    Vigh L, Escriba PV, Sonnleiter A, Piotto S, Maresca B et al (2005) The significance of lipid composition for membrane activity: new concepts and ways of assessing function. Prog Lipid Res 44:303–344

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Calder PC (2006) n-3 Polyunsaturated fatty acids, inflammation and inflammatory diseases. Am J Clin Nutr 83:1505S–1519S

    CAS  PubMed  Google Scholar 

  14. 14.

    Harris WS (2007) Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor. Pharmacol Res 55:217–223

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Deckelbaum RJ, Worgall TS, Seo T (2006) n-3 Fatty acids and gene expression. Am J Clin Nutr 83:1520S–1525S

    CAS  PubMed  Google Scholar 

  16. 16.

    West SG (2002) Rheumatology secrets, 2nd edn. Hanley and Belfus, Philadelphia

    Google Scholar 

  17. 17.

    Percival T (1783) Observations on the medicinal uses of the Oleum Jecoris Aselli, or cod liver oil in the chronic rheumatism and other painful disorders. London Med J 3:393–401

    Google Scholar 

  18. 18.

    Kremer JM (2000) n-3 Fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 71:349S–351S

    CAS  PubMed  Google Scholar 

  19. 19.

    Cleland LG, James MJ (2000) Fish oil and rheumatoid arthritis: anti-inflammatory and collateral health benefits. J Rheumatol 27:2305–2307

    CAS  PubMed  Google Scholar 

  20. 20.

    Sundrarjun T, Komindr S, Archararit N, Dahlan W, Puchaiwatananon O et al (2004) Effects of n-3 fatty acids on serum interleukin-6, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor p55 in active rheumatoid arthritis. J Int Med Res 32:443–454

    CAS  PubMed  Google Scholar 

  21. 21.

    James MJ, Proudmann SM, Cleland LG (2003) Dietary n-3 fats as adjunctive therapy in a prototypic inflammatory disease: issues and obstacles for use in rheumatoid arthritis. Prostaglandins Leukotr Essential Fatty Acids 68:399–405

    Article  CAS  Google Scholar 

  22. 22.

    Calder PC (1997) n-3 Polyunsaturated fatty acids and cytokine production in health and disease. Ann Nutr Metab 41:203–234

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Smith WL (2007) Nutritionally essential fatty acids and biologically-indispensable cyclooxygenases. Trends Biochem Sci 33:27–37

    Article  PubMed  Google Scholar 

  24. 24.

    Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T et al (2000) Gastrointestinal toxicity with celecoxib vs non-steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study; a randomised controlled trial. Celecoxib long-term arthritis safety study. JAMA 284:1247–1255

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    de Boer TN, Huisman AM, Polak AA, Niehoff AG, van Rinsum RC et al (2009) The chondroprotective effect of selective COX-2 inhibition in osteoarthritis: ex vivo evaluation of human cartilage tissue after in vivo treatment. Osteoarthr Cartilage 17:482–488

    Article  Google Scholar 

  26. 26.

    Kang Y-J, Mbonye UR, DeLong CJ, Wada M, Smith WL (2007) Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 46:108–125

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Bagga D, Wag L, Farias-Eisner R, Glaspy JA, Reddy ST (2003) Differential aspects of prostaglandins derived from n-6 and n-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci USA 100:1751–1756

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Massaro M, Habib A, Lubrano L, Del Turco S, Lazzerini G et al (2006) The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKCE inhibition. Proc Natl Acad Sci USA 103:15184–15189

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Badawi AF, El-Sohemy A, Stephen LL, Ghoshal AK, Archer MC (1998) The effect of dietary n-3 and n-6 polyunsaturated fatty acids on the expression of cyclooxygenase 1 and 2 and levels of p21ras in rat mammary glands. Carcinogenesis 19:905–910

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Calviello G, Resci F, Serini S, Piccioni E, Toesca A et al (2007) Docosahexaenoic acid induces proteasome-dependent degradation of ß-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. Carcinogenesis 28:1202–1209

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Llor X, Pons E, Roca A, Alvarez M, Mane J et al (2003) The effects of fish oil, olive oil, oleic acid and linoleic acid on colorectal neoplastic processes. Clin Nutr 22:71–79

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Denkins Y, Kempf D, Ferniz M, Nileshwar S, Marchetti D (2005) Role of n-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma. J Lipid Res 46:1278–1284

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Vecchini A, Ceccarelli V, Susta F, Caligiana P, Orvietani P et al (2004) Dietary alpha-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells. J Lipid Res 45:308–316

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Munsterman AS, Bertone AL, Zachos TA, Weisbrode SE (2005) Effects of the omega-3 fatty acid, α-linolenic acid, on lipopolysaccharide-challenged synovial explants from horses. Am J Vet Res 66:1503–1508

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Hughes CE, Little CB, Buttner FH, Bartnik E, Caterson B (1998) Differential expression of aggrecanase and matrix metalloproteinase activity in chondrocytes isolated from bovine and porcine articular cartilage. J Biol Chem 273:30576–30582

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Zainal Z, Longman AJ, Hurst S, Duggan K, Caterson B et al (2009) Relative efficacies of omega-3 polyunsaturated fatty acids in reducing expression of key proteins in a model system for studying osteoarthritis. Osteoarthr Cartilage 17:882–891

    CAS  Google Scholar 

  37. 37.

    Rees SG, Flannery CR, Little CB, Hughes CE, Caterson B, Dent C (2000) Catabolism of aggrecan, decorin and biglycan in tendon. Biochem J 350:181–188

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Thomas B, Thirion S, Humbert L, Tan L, Goldring MB et al (2002) Differentiation regulates interleukin-1β-induced cyclooxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase. Biochem J 362:367–373

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Arkill KP, Winlove CP (2006) Fatty acid transport in articular cartilage. Arch Biochem Biophys 456:71–78

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Caterson B, Flannery CR, Hughes CE, Little CB (2000) Mechanisms involved in cartilage proteoglycan metabolism. Matrix Biol 19:333–344

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Barbieri SS, Weksler BB (2007) Tobacco smoke cooperates with interleukin-1β to alter β-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo. FASEB J 21:1831–1843

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Bordoni A, Astolfi A, Morandi L, Pession A, Danesi F et al (2007) N-3 PUFAs modulate global gene expression profile in cultured rat cardiomyocytes. Implications for cardiac hypertrophy and heart failure. FEBS Lett 581:923–929

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Sierra S, Lara-Villoslada F, Comalada M, Olivares M, Xaus J (2006) Dietary fish oil n-3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation. Lipids 41:1115–1125

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Connor KP, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J et al (2007) Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 13:868–873

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Moghaddami N, Irvine J, Gao X, Grover PK, Costabile M et al (2007) Novel action of n-3 polyunsaturated fatty acids. Arth Rheum 56:799–808

    Article  CAS  Google Scholar 

  46. 46.

    Bryan D-L, Forsyth KD, Hart PH, Gibson RA (2006) Polyunsaturated fatty acids regulate cytokine and prostaglandin E2 production by respiratory cells in response to mast cell mediators. Lipids 41:1101–1107

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P et al (2003) Differential modulations of toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44:479–486

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Denys A, Hichami A, Khan NA (2005) n-3 PUFAs modulate T-cell activation via protein kinase C-α and -ε and the NFkβ signalling pathway. J Lipid Res 46:752–758

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Roman-Blas JA, Jimenez SA (2006) NFkβ as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthr Cartilage 14:839–848

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This investigation was supported financially by the Arthritis Research Campaign and the Biotechnology and Biological Sciences Research Council (Grant D16961) for which we are grateful.

Author information

Affiliations

Authors

Corresponding author

Correspondence to John L. Harwood.

About this article

Cite this article

Hurst, S., Rees, S.G., Randerson, P.F. et al. Contrasting Effects of n-3 and n-6 Fatty Acids on Cyclooxygenase-2 in Model Systems for Arthritis. Lipids 44, 889 (2009). https://doi.org/10.1007/s11745-009-3347-x

Download citation

Keywords

  • Cyclooxygenase-2 (COX-2) expression
  • COX-2 activity
  • Arthritis
  • n-3 Polyunsaturated fatty acids