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Important Differences Exist in the Dose–Response Relationship between Diet and Immune Cell Fatty Acids in Humans and Rodents

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Lipids

Abstract

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are noted for their ability to diminish inflammatory and immune responses in vitro and in a variety of animal-based models of autoimmunity and inflammation. Yet, recent systematic reviews suggest that the evidence for these fatty acids having beneficial effects on inflammation or autoimmunity in humans is equivocal. A possible explanation for these disappointing and somewhat paradoxical findings emerged from the analyses described in this review. The available data on the changes in immune cell fatty acid profiles in mice, rats and humans, fed various forms and amounts of n-3 PUFA are summarized and displayed graphically. The dose–response curves generated provide new insights into the relationship between dietary n-3 PUFA and immune cell fatty acid profiles. The author suggests that the poor predictive value of most in vitro as well as many animal trials may, in part, be a consequence of the frequent adoption of experimental conditions that create differences in immune cell fatty acid profiles that far exceed what is possible in free-living humans through dietary intervention. Recommendations for improving the preclinical value of future in vitro and animal-based studies with n-3 PUFA are provided.

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Abbreviations

AA:

Arachidonic acid

DHA:

Docosahexaenoic acid

DPA:

Docosapentaenoic acid

en%:

Energy percent

EPA:

Eicosapentaenoic acid

HUFA:

Highly unsaturated fatty acids

ALA:

Alpha-linolenic acid

Mϕ:

Macrophages

PBMC:

Peripheral blood mononuclear cells

PUFA:

Polyunsaturated fatty acids

n-3:

omega-3

n-6:

omega-6

SDA:

Stearidonic acid

References

  1. Meade CJ, Mertin J (1978) Fatty acids and immunity. Adv Lipid Res 16:127–165

    PubMed  CAS  Google Scholar 

  2. Innis SM (2000) Essential fatty acids in infant nutrition: lessons and limitations from animal studies in relation to studies on infant fatty acid requirements. Am J Clin Nutr 71:238S–244S

    PubMed  CAS  Google Scholar 

  3. Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, Hargrove RL, Zhao G, Etherton TD (2000) Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 71:179S–188S

    PubMed  CAS  Google Scholar 

  4. Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PR (2003) Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids. Lipids 38:391–398

    Article  PubMed  CAS  Google Scholar 

  5. Simopoulos AP (2002) Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21:495–505

    PubMed  CAS  Google Scholar 

  6. Lands WE (2005) Dietary fat and health: the evidence and the politics of prevention: careful use of dietary fats can improve life and prevent disease. Ann N Y Acad Sci 1055:179–192

    Article  PubMed  CAS  Google Scholar 

  7. Bates EJ (1995) Eicosanoids, fatty acids and neutrophils: their relevance to the pathophysiology of disease. Prostaglandins Leukot Essent Fatty Acids 53:75–86

    Article  PubMed  CAS  Google Scholar 

  8. Miles EA, Aston L, Calder PC (2003) In vitro effects of eicosanoids derived from different 20-carbon fatty acids on T helper type 1 and T helper type 2 cytokine production in human whole-blood cultures. Clin Exp Allergy 33:624–632

    Article  PubMed  CAS  Google Scholar 

  9. Serhan CN, Arita M, 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  PubMed  CAS  Google Scholar 

  10. Serhan CN (2005) Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins. Curr Opin Clin Nutr Metab Care 8:115–121

    Article  PubMed  CAS  Google Scholar 

  11. Lands WE, Morris A, Libelt B (1990) Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues. Lipids 25:505–516

    Article  PubMed  CAS  Google Scholar 

  12. Lands WE, Libelt B, Morris A, Kramer NC, Prewitt TE, Bowen P, Schmeisser D, Davidson MH, Burns JH (1992) Maintenance of lower proportions of (n-6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n-3) fatty acids. Biochim Biophys Acta 1180:147–162

    PubMed  CAS  Google Scholar 

  13. Marangoni F, Angeli MT, Colli S, Eligini S, Tremoli E, Sirtori CR, Galli C (1993) Changes of n-3 and n-6 fatty acids in plasma and circulating cells of normal subjects, after prolonged administration of 20:5 (EPA) and 22:6 (DHA) ethyl esters and prolonged washout. Biochim Biophys Acta 1210:55–62

    PubMed  CAS  Google Scholar 

  14. Gibney MJ, Hunter B (1993) The effects of short- and long-term supplementation with fish oil on the incorporation of n-3 polyunsaturated fatty acids into cells of the immune system in healthy volunteers. Eur J Clin Nutr 47:255–259

    PubMed  CAS  Google Scholar 

  15. Lokesh BR, German B, Kinsella JE (1988) Differential effects of docosahexaenoic acid and eicosapentaenoic acid on suppression of lipoxygenase pathway in peritoneal macrophages. Biochim Biophys Acta 958:99–107

    PubMed  CAS  Google Scholar 

  16. Fujikawa M, Yamashita N, Yamazaki K, Sugiyama E, Suzuki H, Hamazaki T (1992) Eicosapentaeoic acid inhibits antigen-presenting cell function of murine splenocytes. Immunology 75:330–335

    PubMed  CAS  Google Scholar 

  17. Trumbo P, Schlicker S, Yates AA, Poos M (2002) Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc 102:1621–1630

    Article  PubMed  Google Scholar 

  18. Hulbert AJ, Rana T, Couture P (2002) The acyl composition of mammalian phospholipids: an allometric analysis. Comp Biochem Physiol B Biochem Mol Biol 132:515–527

    Article  PubMed  CAS  Google Scholar 

  19. Turner N, Haga KL., Hulbert AJ, Else PL (2005) Relationship between body size, Na+-K+-ATPase activity, and membrane lipid composition in mammal and bird kidney. Am J Physiol Regul Integr Comp Physiol 288:R301–R310

    PubMed  CAS  Google Scholar 

  20. Kew S, Banerjee T, Minihane AM, Finnegan YE, Williams CM, Calder PC (2003) Relation between the fatty acid composition of peripheral blood mononuclear cells and measures of immune cell function in healthy, free-living subjects aged 25–72 y. Am J Clin Nutr 77:1278–1286

    PubMed  CAS  Google Scholar 

  21. Nakamura MT, Nara TY (2003) Essential fatty acid synthesis and its regulation in mammals. Prostaglandins Leukot Essent Fatty Acids 68:145–150

    Article  PubMed  CAS  Google Scholar 

  22. Brenner RR (1987) Biosynthesis and interconversion of the essential fatty acids. In: Willis AL (eds) CRC handbook of eicosanoids: prostaglandins and related lipids, 1 edn. CRC, Boca Raton, pp 99–117

    Google Scholar 

  23. Cho HP, Nakamura MT, Clarke SD (1999) Cloning, expression, and nutritional regulation of the mammalian delta-6 desaturase. J Biol Chem 274:471–477

    Article  PubMed  CAS  Google Scholar 

  24. Ursin VM (2003) Modification of plant lipids for human health: development of functional land-based omega-3 fatty acids. J Nutr 133:4271–4274

    PubMed  CAS  Google Scholar 

  25. Miles EA, Banerjee T, Dooper MM, M’Rabet L, Graus YM, Calder PC (2004) The influence of different combinations of gamma-linolenic acid, stearidonic acid and EPA on immune function in healthy young male subjects. Br J Nutr 91:893–903

    Article  PubMed  CAS  Google Scholar 

  26. Liu H, Pope RM (2004) Phagocytes: mechanisms of inflammation and tissue destruction. Rheum Dis Clin North Am 30:19–39

    Article  PubMed  Google Scholar 

  27. Fujiwara N, Kobayashi K (2005) Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 4:281–286

    Article  PubMed  CAS  Google Scholar 

  28. Fritsche KL, McGuire SO (1996) The adverse effects of an in vivo inflammatory challenge on the vitamin E status of rats is accentuated by fish oil feeding. J Nutr Biochem 7:623–631

    Article  CAS  Google Scholar 

  29. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  PubMed  CAS  Google Scholar 

  30. Abe M, Takahashi H, Gouya T, Nagata N, Shigematsu N (1990) Enhanced superoxide anion generation but reduced leukotriene B4 productivity in thioglycollate-elicited peritoneal macrophages. Prostaglandins Leukot Essent Fatty Acids 40:109–115

    Article  PubMed  CAS  Google Scholar 

  31. Hardardottir I, Whelan J, Surette ME, Broughton KS, GuoPing L, Larsen EC, Kinsella JE (1993) The effects of dietary n-3 polyunsaturated fatty acids and cyclic AMP-elevating agents on tumor necrosis factor production by murine-resident and thioglycollate-elicited peritoneal macrophages. J Nutr Biochem 4:534–542

    Article  CAS  Google Scholar 

  32. Whelan J, Golemboski KA, Broughton KS, Kinsella JE, Dietert RR (1997) Characterization of leukotriene production in vivo and in vitro in resident and elicited peritoneal macrophages in chickens and mice. Prostaglandins Leukot Essent Fatty Acids 56:41–49

    Article  PubMed  CAS  Google Scholar 

  33. Black JM, Kinsella JE (1993) Dietary n-3 fatty acids alter murine peritoneal macrophage cytotoxicity. Ann Nutr Metab 37:110–120

    Article  PubMed  CAS  Google Scholar 

  34. Whelan J, Broughton KS, Kinsella JE (1991) The comparative effects of dietary alpha-linolenic acid and fish oil on 4- and 5-series leukotriene formation in vivo. Lipids 26:119–126

    Article  PubMed  CAS  Google Scholar 

  35. Brouard C, Pascaud M (1993) Modulation of rat and human lymphocyte function by n-6 and n-3 polyunsaturated fatty acids and acetylsalicylic acid. Ann Nutr Metab 37:146–159

    PubMed  CAS  Google Scholar 

  36. Whelan J, Broughton KS, Surette ME, Kinsella JE (1992) Dietary arachidonic and linoleic acids: comparative effects on tissue lipids. Lipids 27:85–88

    Article  PubMed  CAS  Google Scholar 

  37. Lokesh BR, Black JM, German JB, Kinsella JE (1988) Docosahexaenoic acid and other dietary polyunsaturated fatty acids suppress leukotriene synthesis by mouse peritoneal macrophages. Lipids 23:968–972

    Article  PubMed  CAS  Google Scholar 

  38. Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, Yaqoob P (2004) Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am J Clin Nutr 79:674–681

    PubMed  CAS  Google Scholar 

  39. Cleland LG, Gibson RA, Hawkes JS, James MJ (1990) Comparison of cell membrane phospholipid fatty acids in five rat strains fed four test diets. Lipids 25:559–564

    Article  PubMed  CAS  Google Scholar 

  40. Surette ME, Edens M, Chilton FH, Tramposch KM (2004) Dietary echium oil increases plasma and neutrophil long-chain (n-3) fatty acids and lowers serum triacylglycerols in hypertriglyceridemic humans. J Nutr 134:1406–1411

    PubMed  CAS  Google Scholar 

  41. James MJ, Gibson RA, D’Angelo M, Neumann MA, Cleland LG (1993) Simple relationships exist between dietary linoleate and the n-6 fatty acids of human neutrophils and plasma. Am J Clin Nutr 58:497–500

    PubMed  CAS  Google Scholar 

  42. Leslie CA, Gonnerman WA, Ullman MD, Hayes KC, Franzblau C, Cathcart ES (1985) Dietary fish oil modulated macrophage fatty acids and decreases arthritis susceptibility in mice. J Exp Med 162:1336–1349

    Article  PubMed  CAS  Google Scholar 

  43. Trebble TM, Arden NK, Wootton SA, Calder PC, Mullee MA, Fine DR, Stroud MA (2004) Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr 80:1137–1144

    PubMed  CAS  Google Scholar 

  44. Huang YS, Mills DE, Ward RP, Horrobin DF, Simmons VA (1989) Effect of essential fatty acid depletion on tissue phospholipid fatty acids in spontaneously hypertensive and normotensive rats. Lipids 24:565–571

    Article  PubMed  CAS  Google Scholar 

  45. Kew S, Banerjee T, Minihane AM, Finnegan YE, Muggli R, Albers R, Williams CM, Calder PC (2003) Lack of effect of foods enriched with plant- or marine-derived n-3 fatty acids on human immune function. Am J Clin Nutr 77:1287–1295

    PubMed  CAS  Google Scholar 

  46. Broughton KS, Morgan LJ (1994) Frequency of (n-3) polyunsaturated fatty acid consumption induces alterations in tissue lipid composition and eicosanoid synthesis in CD-1 mice. J Nutr 124:1104–1111

    PubMed  CAS  Google Scholar 

  47. Wallace FA, Miles EA, Calder PC (2003) Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Br J Nutr 89:679–689

    Article  PubMed  CAS  Google Scholar 

  48. Huang SC, Fritsche KL (1992) Alteration in mouse splenic phospholipid fatty acid composition and lymphoid cell populations by dietary fat. Lipids 27:25–32

    Article  PubMed  CAS  Google Scholar 

  49. Fritsche K (2006) Fatty acids as modulators of the immune response. Annu Rev Nutr 26:45–73

    Article  PubMed  CAS  Google Scholar 

  50. Kang JX, Wang J, Wu L, Kang ZB (2004) Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids. Nature 427:504

    Article  PubMed  CAS  Google Scholar 

  51. Xia S, Lu Y, Wang J, He C, Hong S, Serhan CN, Kang JX (2006) Melanoma growth is reduced in fat-1 transgenic mice: impact of omega-6/omega-3 essential fatty acids. Proc Natl Acad Sci U S A 103:12499–12504

    Article  PubMed  CAS  Google Scholar 

  52. Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, Serhan CN, Kang JX (2006) Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc Natl Acad Sci U S A 103:11276–11281

    Article  PubMed  CAS  Google Scholar 

  53. Lai L, Kang JX, Li R, Wang J, Witt WT, Yong HY, Hao Y, Wax DM, Murphy CN, et al. (2006) Generation of cloned transgenic pigs rich in omega-3 fatty acids. Nat Biotechnol 24:435–436

    Article  PubMed  CAS  Google Scholar 

  54. Hawkes JS, Bryan DL, Makrides M, Neumann MA, Gibson RA (2002) A randomized trial of supplementation with docosahexaenoic acid-rich tuna oil and its effects on the human milk cytokines interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha. Am J Clin Nutr 75:754–760

    PubMed  CAS  Google Scholar 

  55. Rees D, Miles EA, Banerjee T, Wells SJ, Roynette CE, Wahle KW, Calder PC (2006) Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 83:331–342

    PubMed  CAS  Google Scholar 

  56. Trebble TM, Arden NK, Wootton SA, Mullee MA, Calder PC, Burdge GC, Fine DR, Stroud MA (2004) Peripheral blood mononuclear cell fatty acid composition and inflammatory mediator production in adult Crohn’s disease. Clin Nutr 23:647–655

    Article  PubMed  CAS  Google Scholar 

  57. Kelley DS, Taylor PC, Nelson GJ, Schmidt PC, Ferretti A, Erickson KL, Yu R, Chandra RK, Mackey BE (1999) Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men. Lipids 34:317–324

    Article  PubMed  CAS  Google Scholar 

  58. Hinds A, Sanders TAB (1993) The effect of increasing levels of dietary fish oil rich in eicosapentaenoic and docosahexaenoic acids on lymphocyte phospholipid fatty acid composition and cell-mediated immunity in the mouse. Br J Nutr 69:423–429

    Article  PubMed  CAS  Google Scholar 

  59. Fritsche KL, Johnston PV (1990) Effect of dietary alpha-linolenic acid on growth, metastasis, fatty acid profile and prostaglandin production of two murine mammary adenocarcinomas. J Nutr 120:1601–1609

    PubMed  CAS  Google Scholar 

  60. VanMeter AR, Ehringer WD, Stillwell W, Blumenthal EJ, Jenski LJ (1994) Aged lymphocyte proliferation following incorporation and retention of dietary omega-3 fatty acids. Mech Ageing Dev 75:95–114

    Article  PubMed  CAS  Google Scholar 

  61. Jenski LJ, Bowker GM, Johnson MA, Ehringer WD, Fetterhoff T, Stillwell W (1995) Docosahexanoic acid-induced alteration of Thy-1 and CD8 expression on murine splenocytes. Biochim Biophys Acta 1236:39–50

    Article  PubMed  Google Scholar 

  62. Chapkin RS, Somers SD, Schumacher L, Erickson KL (1988) Fatty acid composition of macrophage phospholipids in mice fed fish or borage oil. Lipids 23:380–383

    Article  PubMed  CAS  Google Scholar 

  63. Brouard C, Pascaud M (1990) Effects of moderate dietary supplementations with n-3 fatty acids on macrophage and lymphocyte phospholipids and macrophage eicosanoid synthesis in the rat. Biochim Biophys Acta 1047:19–28

    PubMed  CAS  Google Scholar 

  64. Jeffery NM, Sanderson P, Sherrington EJ, Newsholme EA, Calder PC (1996) The ratio of n-6 to n-3 polyunsaturated fatty acids in the rat diet alters serum lipid levels and lymphocyte functions. Lipids 31:737–745

    Article  PubMed  CAS  Google Scholar 

  65. Yaqoob P, Newsholme EA, Calder PC (1995) Influence of cell culture conditions in diet-induced changes in lymphocyte fatty acid composition. Biochim Biophys Acta 1255:333–340

    PubMed  Google Scholar 

  66. Kleemann R, Scott FW, Worz-Pagenstert U, Nimal Ratnayake WM, Kolb H (1998) Impact of dietary fat on Th1/Th2 cytokine gene expression in the pancreas and gut of diabetes-prone BB rats. J Autoimmun 11:97–103

    Article  PubMed  CAS  Google Scholar 

  67. Fisher M, Levine PH, Weiner BH, Johnson MH, Doyle EM, Ellis PA, Hoogasian JJ (1990) Dietary n-3 fatty acid supplementation reduces superoxide production and chemiluminescence in a monocyte-enriched preparation of leukocytes. Am J Clin Nutr 51:804–808

    PubMed  CAS  Google Scholar 

  68. Mitjavila MT, Rodriguez MC, Saiz MP, Lloret S, Moreno JJ (1996) Effect of degree of unsaturation in dietary fatty acids on arachidonic acid mobilization by peritoneal macrophages. Lipids 31:661–666

    Article  PubMed  CAS  Google Scholar 

  69. Broughton KS, Whelan J, Hardardottir I, Kinsella JE (1991) Effect of increasing the dietary (n-3) to (n-6) polyunsaturated fatty acid ratio on murine liver and peritoneal cell fatty acids and eicosanoid formation. J Nutr 121:155–164

    PubMed  CAS  Google Scholar 

  70. Somers SD, Chapkin RS, Erickson KL (1989) Alteration of in vitro murine peritoneal macrophage function by dietary enrichment with eicosapentaenoic and docosahexaenoic acids in menhaden fish oil. Cell Immunol 123:201–211

    Article  PubMed  CAS  Google Scholar 

  71. James MJ, Cleland LG, Gibson RA, Hawkes JS (1991) Interaction between fish and vegetable oils in relation to rat leucocyte leukotriene production. J Nutr 121:631–637

    PubMed  CAS  Google Scholar 

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Acknowledgments

The author is grateful to Dr. Jay Whelan (University of Tennessee) for his inspiration and advice regarding this manuscript.

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  1. University of Missouri, Columbia, MO, USA

    Kevin Fritsche

  2. 110 Animal Science Center, 920 East Campus Drive, Columbia, MO, 65211-0001, USA

    Kevin Fritsche

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Fritsche, K. Important Differences Exist in the Dose–Response Relationship between Diet and Immune Cell Fatty Acids in Humans and Rodents. Lipids 42, 961–979 (2007). https://doi.org/10.1007/s11745-007-3106-9

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