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Eicosapentaenoic and docosahexaenoic acids alter rat spleen leukocyte fatty acid composition and prostaglandin E2 production but have different effects on lymphocyte functions and cell-mediated immunity

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Lipids

Abstract

Weanling rats were fed on high-fat (178 g/kg) diets which contained 4.4 g α-linolenic (ALA), γ-linolenic, arachidonic (ARA), eicosapentaenoic (EPA), or docosahexaenoic acid (DHA)/100 g total fatty acids. The proportions of all other fatty acids, apart from linoleic acid, and the proportion of total polyunsaturated fatty acids (PUFA) (approximately 35 g/100 g total fatty acids) were constant, and the n−6 to n−3 PUFA ratio was maintained as close to 7 as possible. The fatty acid compositions of the serum and of spleen leukocytes were markedly influenced by that of the diet. Prostaglandin E2 production was enhanced from leukocytes from rats fed the ARA-rich diet and was decreased from leukocytes from the EPA- or DHA-fed rats. Replacing dietary ALA with EPA resulted in diminished ex vivo lymphocyte proliferation and natural killer (NK) cell activity and a reduced cell-mediated immune response in vivo. In contrast, replacing ALA with DHA reduced ex vivo lymphocyte proliferation but did not affect ex vivo NK cell activity or the cell-mediated immune response in vivo. Replacement of a proportion of linoleic acid with either γ-linolenic acid or ARA did not affect lymphocyte proliferation, NK cell activity, or the cell-mediated immune response. Thus, this study shows that different n−3 PUFA exert different immunomodulatory actions, that EPA exerts more widespread and/or stronger immunomodulatory effects than DHA, that a low level of EPA is sufficient to influence the immune response, and that the immunomodulatory effects of fish oil may be mainly due to EPA.

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Abbreviations

ALA:

α-hnolenic acid

ARA:

arachidonic acid

Con A:

concanavalin A

DHA:

docosahexaenoic acid

EPA:

eicosapentaenoic acid

GLA:

γ-linolenic acid

NK:

natural killer

PBS:

phosphate-buffered saline

PG:

prostaglandin

PLN:

popliteal lymph node

PUFA:

polyunsaturated fatty acid

SO:

safflower oil

References

  1. Goldyne, M.E., and Stobo, J.D. (1981) Immunoregulatory Role of Prostaglandins and Related Lipids, Crit. Rev. Immunol. 2, 189–223.

    CAS  Google Scholar 

  2. Goodwin, J.S., and Cueppens, J. (1983) Regulation of the Immune Response by Prostaglandins, J. Clin. Immunol. 3, 295–315.

    Article  PubMed  CAS  Google Scholar 

  3. Hwang, D. (1989) Essential Fatty Acids and the Immune Response, FASEB J. 3, 2052–2061.

    PubMed  CAS  Google Scholar 

  4. Kromann, N., and Green, A. (1980) Epidemiological Studies in the Upernavik District, Greenland, Acta Med. Scand. 208, 401–406.

    Article  PubMed  CAS  Google Scholar 

  5. Kremer, J.M., Lawrence, D.A., Jubiz, W., Di Giacomo, R., Rynes, K., Bartholomew, L.E., and Sherman, M. (1990) Dietary Fish Oil and Olive Oil Supplementation in Pateints with Rheumatoid Arthritis, Arthritis Rheum. 33, 810–820.

    PubMed  CAS  Google Scholar 

  6. Sperling, R.I., Weinblatt, M.E., Robin, J.L., Ravalese, J., Hoover, R.L., House, F., Coblyn, J.S., Fraser, P.A., Spur, B.W., Robinson, D.R., Lewis, R.A., and Austen, K.F. (1987) Effects of Dietary Supplementation with Marine Fish Oil on Leukocyte Lipid Mediator Generation and Function in Rheumatoid Arthritis, Arthritis Rheum. 30, 987–988.

    Google Scholar 

  7. Cleland, L.G., French, J.K., Betts, W.H., Murphy, G.A., and Elliott, M.J. (1988) Clinical and Biochemical Effects of Dietary Fish Oil Supplements in Rheumatoid Arthritis, J. Rheumatol. 15, 1471–1475.

    PubMed  CAS  Google Scholar 

  8. Ziboh, V.A., Cohen, K.A., Ellis, C.N., Miller, C., Hamilton, T.A., Kragballe, K., Hydrick, C.R., and Voorhees, J.J. (1986) Effects of Dietary Supplementation of Fish Oil on Neutrophil and Epidermal Fatty Acids: Modulation of Clinical Course of Psoriatic Lesions, Arch. Dermatol. 122, 1277–1282.

    Article  PubMed  CAS  Google Scholar 

  9. Das, U.N. (1994) Beneficial Effect of Eicosapentaenoic and Docosahexaenoic Acids in the Management of Systemic Lupus Erythematosus and Its Relationship to the Cytokine Network, Prostaglandins Leukotrienes Essent. Fatty Acids 51, 207–213.

    Article  CAS  Google Scholar 

  10. Hawthorne, A.B., Daneshmend, T.K., Hawkey, C.J., Belluzzi, A., Everitt, S.J., Holmes, G.K.T., Malkinson, C., Shaheen, M.Z., and Willars, J.E. (1992) Treatment of Ulcerative Colitis with Fish Oil Supplementation: A Prospective 12 Month Randomised Controlled Trial, Gut 33, 922–928.

    PubMed  CAS  Google Scholar 

  11. Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., and Miglioloi, M. (1996) Effect of an Enteric-Coated Fish Oil Preparation on Relapses in Crohn's Disease, New Engl. J. Med. 334, 1557–1560.

    Article  PubMed  CAS  Google Scholar 

  12. Homan van der Heide, J.J., Bilo, H.J.G., Donker, J.M., Wilmink, J.M., and Tegzess, A.M. (1983) Effect of Dietary Fish Oil on Renal Function and Rejection in Cyclosporine-Treated Recipients of Renal Transplants, New Engl. J. Med. 329, 769–773.

    Article  Google Scholar 

  13. Gurr, M.I. (1983) The Role of Lipids in the Regulation of the Immune System, Prog. Lipid Res. 22, 257–287.

    Article  PubMed  CAS  Google Scholar 

  14. Calder, P.C. (1995) Fatty Acids, Dietary Lipids and Lymphocyte Functions, Biochem. Soc. Trans. 23, 302–309.

    PubMed  CAS  Google Scholar 

  15. Calder, P.C. (1996) Can n−3 Polyunsaturated Fatty Acids Be Used as Immunomodulatory Agents? Biochem. Soc. Trans. 24, 211–220.

    PubMed  CAS  Google Scholar 

  16. Calder, P.C. (1996) Effects of Fatty Acids and Dietary Lipids on Cells of the Immune System, Proc. Nutr. Soc. 55, 127–150.

    PubMed  CAS  Google Scholar 

  17. Calder, P.C. (1996) Immunomodulatory and Anti-Inflammatory Effects of Omega-3 Polyunsaturated Fatty Acids, Proc. Nutr. Soc. 55, 737–774.

    Article  PubMed  CAS  Google Scholar 

  18. Calder, P.C. (1998) Dietary Lipids and the Immune System. Nutr. Rev., in press.

  19. Calder, P.C. (1997) n-3 Polyunsaturated Fatty Acids and Cytokine Production in Health and Disease, Ann. Nutr. Metab. 41, 203–234.

    PubMed  CAS  Google Scholar 

  20. Marshall, L.A., and Johnston, P.V. (1985) The Influence of Dietary Essential Fatty Acids on Rat Immunocompetent Cell Prostaglandin Synthesis and Mitogen-Induced Blastogenesis, J. Nutr. 115, 1572–1580.

    PubMed  CAS  Google Scholar 

  21. Kelley, D.S., Nelson, G.J., Serrato, C.M., Schmidt, P.C., and Branch, L.B. (1988) Effects of Type of Dietary Fat on Indices of Immune Status of Rabbits, J. Nutr. 118, 1376–1384.

    PubMed  CAS  Google Scholar 

  22. Fritsche, K.L., Cassity, N.A., and Huang, S.-C. (1991) Effect of Dietary Fat Source on Antibody Production and Lymphocyte Proliferation in Chickens, Poultry Sci. 70, 611–617.

    CAS  Google Scholar 

  23. Yaqoob, P., Newsholme, E.A., and Calder, P.C. (1994) The Effect of Dietary Lipid Manipulation on Rat Lymphocyte Subsets and Proliferation, Immunology 82, 603–610.

    PubMed  CAS  Google Scholar 

  24. Calder, P.C., Costa-Rosa, L.F.B.P., and Curi, R. (1995) Effects of Feeding Lipids of Different Fatty Acid Compositions upon Rat Lymphocyte Proliferation, Life Sci., 56, 455–463.

    Article  PubMed  CAS  Google Scholar 

  25. Yaqoob, P., and Calder, P.C. (1995) The Effects of Dietary Lipid Manipulation on the Production of Murine T-Cell-Derived Cytokines, Cytokine 7, 548–553.

    Article  PubMed  CAS  Google Scholar 

  26. Sanderson, P., Yaqoob, P., and Calder, P.C. (1995) Effects of Dietary Lipid Manipulation upon Rat Spleen Lymphocyte Functions and the Expression of Lymphocyte Surface Molecules, J. Nutr. Environ. Med. 5, 119–132.

    CAS  Google Scholar 

  27. Jeffery, N.M., Sanderson, P., Sherrington, E.J., Newsholme, E.A., and Calder, P.C. (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 

  28. Erickson, K.L. (1984) Dietary Fat Influences on Murine Melanoma Growth and Lymphocyte-Mediated Cytotoxicity, J. Natl. Cancer Inst. 72, 115–120.

    PubMed  CAS  Google Scholar 

  29. Olson, L.M., Clinton, S.K., Everitt, J.I., Johnston, P.V., and Visek, W.J. (1987) Lymphocyte Activation, Cell-Mediated Cytotoxicity and Their Relationship to Dietary Fat-Enhanced Mammary Tumorigenesis in C3H/OUJ Mice, J. Nutr. 117, 955–963.

    PubMed  CAS  Google Scholar 

  30. Fritsche, K.L., and Johnston, P.V. (1989) Modulation of Eicosanoid Production and Cell-Mediated Cytotoxicity by Dietary α-Linolenic Acid in BALB/c Mice, Lipids 24, 305–311.

    PubMed  CAS  Google Scholar 

  31. Fritsche, K.L., and Johnston, P.V. (1990) Effect of Dietary Omega-3 Fatty Acids on Cell-Mediated Cytotoxicity in BALB/c Mice, Nutr. Res. 10, 577–588.

    Article  CAS  Google Scholar 

  32. Fritsche, K.L., and Cassity, N.A. (1992) Dietary n−3 Fatty Acids Reduce Antibody-Dependent Cell Cytotoxicity and Alter Eicosanoid Release by Chicken Immune Cells, Poultry Sci. 71, 1646–1657.

    CAS  Google Scholar 

  33. Meydani, S.N., Yogeeswaran, G., Liu, S., Baskar, S., and Meydani, M. (1988) Fish Oil and Tocopherol-Induced Changes in Natural Killer Cell-Mediated Cytotoxicity and PGE2 Synthesis in Young and Old Mice, J. Nutr. 118, 1245–1252.

    PubMed  CAS  Google Scholar 

  34. Berger, A., German, J.B., Chiang, B.L., Ansari, A.A., Keen, C.L., Fletcher, M.P., and Gershwin, M.R. (1993) Influence of Feeding Unsaturated Fats on Growth and Immune Status of Mice, J. Nutr. 123, 225–233.

    PubMed  CAS  Google Scholar 

  35. Yaqoob, P., Newsholme, E.A., and Calder, P.C. (1994) Inhibition of Natural Killer Cell Activity by Dietary Lipids, Immunol. Lett. 41, 241–247.

    Article  PubMed  CAS  Google Scholar 

  36. Mertin, J., Stackpole, A., and Shumway, S. (1985) Nutrition and Immunity: The Immunoregulatory Effect of n−6 Essential Fatty Acids Is Mediated Through Prostaglandin E, Int. Arch. Allergy Appl. Immunol. 77, 390–395.

    PubMed  CAS  Google Scholar 

  37. Hinds, A., and Sanders, T.A.B. (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 

  38. Sanderson, P., Yaqoob, P., and Calder, P.C. (1995) Effects of Dietary Lipid Manipulation upon Graft vs. Host and Host vs. Graft Responses in the Rat, Cell. Immunol. 164, 240–247.

    Article  PubMed  CAS  Google Scholar 

  39. Jeffery, N.M., Newsholme, E.A., and Calder, P.C. (1997) The Level of Polyunsaturated Fatty Acids and the n−6 to n−3 Polyunsaturated Fatty Acid Ratio in the Rat Diet Both Affect Serum Lipid Levels and Lymphocyte Functions, Prostaglandins Leukotrienes Essent. Fatty Acids 57, 149–160.

    Article  CAS  Google Scholar 

  40. Jeffery, N.M., Yaqoob, P., Newsholme, E.A., and Calder, P.C. (1996) The Effects of Olive Oil upon Rat Serum Lipid Levels and Lymphocyte Functions Appear to Be Due to Oleic Acid, Ann. Nutr. Metab. 40, 71–80.

    PubMed  CAS  Google Scholar 

  41. Jeffery, N.M., Sanderson, P., Newsholme, E.A., and Calder, P.C. (1997) Effects of Varying the Type of Saturated Fatty Acid in the Rat Diet upon Serum Lipid Levels and Spleen Lymphocyte Functions, Biochim. Biophys. Acta, 1345, 223–236.

    PubMed  CAS  Google Scholar 

  42. Jeffery, N.M., Cortina, M., Newsholme, E.A., and Calder, P.C. (1997) Effects of Variations in the Proportions of Saturated. Monounsaturated and Polyunsaturated Fatty Acids in the Rat Diet upon Spleen Lymphocyte Functions, Br. J. Nutr. 77, 805–823.

    Article  PubMed  CAS  Google Scholar 

  43. Nassar, B.A., Huang, Y.S., Manku, M.S., Das, U.N., Morse, N., and Horrobin, D.F. (1986) The Influence of Dietary Manipulation with n−3 and n−6 Fatty Acids on Liver and Plasma Phospholipid Fatty Acids in Rats, Lipids 21, 652–656.

    PubMed  CAS  Google Scholar 

  44. Brenner, R.R., and Peluffo, R.O. (1967) Inhibitory Effect of Docosa-4,7,10,13,16,19-hexaenoic Acid upon the Oxidative Desaturation of Linoleic into Gamma-Linolenic Acid and of Alpha-Linolenic Acid into Octa-6,9,12,15-tetraenoic Acid, Biochim. Biophys. Acta 137, 184–186.

    PubMed  CAS  Google Scholar 

  45. Jensen, M.M., Christensen, M.S., and Hoy, C-E. (1994) Intestinal Absorption of Octanoic, Decanoic and Linoleic Acids: Effect of Triglyceride Structure, Ann. Nutr. Metab. 38, 104–116.

    Article  PubMed  CAS  Google Scholar 

  46. Whelan, J., Surette, M.E., Hardardottir, I., Lu, G., Golemboski, K.A., Larsen, E., and Kinsella, J.E. (1993) Dietary Arachidonate Enhances Tissue Arachidonate Levels and Eicosanoid Production in Syrian Hamsters, J. Nutr. 123, 2174–2185.

    PubMed  CAS  Google Scholar 

  47. Goldyne, M.E. (1988) Lymphocytes and Arachidonic Acid Metabolism, Prog. Allergy 44, 140–152.

    PubMed  CAS  Google Scholar 

  48. Report of the Cardiovascular Review Group Committee on Medical Aspects of Food Policy (1994) Nutritional Aspects of Cardiovascular Disease, p. 23, HMSO Publications, London.

  49. Report of the British Nutrition Foundation's Task Force (1992) Unsaturated Fatty Acids: Nutritional and Physiological Significance, pp. 12–19, Chapman & Hall, London.

  50. Meydani, S.N., Endres, S., Woods, M.M., Goldin, B.R., Soo, C., Morrill-Labrode, A., and Dinarello, C. (1991) Gral (n-3) Fatty Acid Supplementation Suppresses Cytokine Production and Lymphocyte Proliferation: Comparison Between Young and Older Women, J. Nutr. 121, 547–555.

    PubMed  CAS  Google Scholar 

  51. Meydani, S.N., Lichtenstein, A.H., Cornwall, S., Meydani, M., Goldin, B.R., Rasmussen, H., Dinarello, C.A., and Schaefer, E.J. (1993) Immunologic Effects of National Cholesterol Education Panel Step-2 Diets With and Without Fish-Derived n−3 Fatty Acid Enrichment, J. Clin. Invest. 92, 105–113.

    PubMed  CAS  Google Scholar 

  52. Endres, S., Meydani, S.N., Ghorbani, R., Schindler, R., and Dinarello, C.A. (1993) Dietary Supplementation with n−3 Fatty Acids Suppresses Interleukin-2 Production and Mononuclear Cell Proliferation, J. Leukocyte Biol. 54, 599–603.

    PubMed  CAS  Google Scholar 

  53. Jolly, C.A., Jiang, Y-H., Chapkin, R.S., and McMurray, D.N. (1997) Dietary (n-3) Polyunsaturated Fatty Acids Suppress Murine Lymphoproliferation, Interleukin-2 Secretion, and the Formation of Diacylglycerol and Ceramide, J. Nutr. 127, 37–43.

    PubMed  CAS  Google Scholar 

  54. Kelley, D.S., Taylor, P.C., Nelson, G.J., Schmidt, P.C., Mackey, B.E., and Kyle, D. (1997) Effects of Dietary Arachidonic Acid on Human Immune Response, Lipids 32, 449–456.

    PubMed  CAS  Google Scholar 

  55. Chang, H.R., Dulloo, A.G., Vladoianu, I.R., Piguet, P.F., Arsenijevic, D., Girardier, L., and Pechere, J.C. (1992) Fish Oil Decreases Natural Resistance of Mice to Infection with Salmonella typhimurium, Metabolism 41, 1–2.

    Article  PubMed  CAS  Google Scholar 

  56. D'Ambola, J.B., Aeberhard, E.E., Trang, N., Gaffar, S., Barrett, C.T., and Sherman, M.P. (1991) Effect of Dietary (n−3) and (n−6) Fatty Acids on In Vivo Pulmonary Bacterial Clearance by Neonatal Rabbits, J. Nutr. 121, 1262–1269.

    PubMed  Google Scholar 

  57. Fritsche, K.L., Shahbazian, L.M., Feng, C., and Berg, J.N. (1997) Dietary Fish Oil Reduces Survival and Impairs Bacterial Clearance in C3H/Hen Mice Challenged with Listeria monocytogenes, Clin. Sci. 92, 95–101.

    PubMed  CAS  Google Scholar 

  58. Soyland, E., Lea, T., Sandstad, B., and Drevon, A. (1994) Dietary Supplementation with Very Long Chain n−3 Fatty Acids in Man Decreases Expression of the Interleukin-2 Receptor (CD25) on Mitogen-Stimulated Lymphocytes from Patients with Inflammatory Skin Diseases, Eur. J. Clin. Invest. 24, 236–242.

    PubMed  CAS  Google Scholar 

  59. Santoli, D., Phillips, P.D., Colt, T.L., and Zurier, R.B. (1990) Suppression of Interleukin-2-Dependent Human T Cell Growth In Vitro by Prostaglandin E (PGE) and Their Precursor Fatty Acids, J. Clin. Invest. 85, 424–432.

    PubMed  CAS  Google Scholar 

  60. Calder, P.C., Bevan, S.J., and Newsholme, E.A. (1992) The Inhibition of T-Lymphocyte Proliferation by Fatty Acids Is Via an Eicosanoid-Independent Mechanism, Immunology 75, 108–115.

    PubMed  CAS  Google Scholar 

  61. Soyland, E., Nenseter, M.S., Braathen, L., and Drevon, C.A. (1993) Very Long Chain n−3 and n−6 Polyunsaturated Fatty Acids Inhibit Proliferation of Human T Lymphocytes in vitro, Eur. J. Clin. Invest. 23, 112–121.

    Article  PubMed  CAS  Google Scholar 

  62. Khalfoun, B., Thibault, G., Lacord, M., Gruel, Y., Bardos, P., and Lebranchu, Y. (1996) Docosahexaenoic and Eicosapentaenoic Acids Inhibit Human Lymphoproliferative Responses In Vitro But Not the Expression of T Cell Surface Activation Markers, Scand. J. Immunol. 43, 248–256.

    PubMed  CAS  Google Scholar 

  63. Wu, D., Meydani, S.N., Meydani, M., Hayek, M.G., Huth, P., and Nicolosi, R.J. (1996) Immunologic Effects of Marine- and Plant-Derived n−3 Polyunsaturated Fatty Acids in Nonhuman Primates, Am. J. Clin. Nutr. 63, 273–280.

    PubMed  CAS  Google Scholar 

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Correspondence to P. C. Calder.

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Peterson, L.D., Jeffery, N.M., Thies, F. et al. Eicosapentaenoic and docosahexaenoic acids alter rat spleen leukocyte fatty acid composition and prostaglandin E2 production but have different effects on lymphocyte functions and cell-mediated immunity. Lipids 33, 171–180 (1998). https://doi.org/10.1007/s11745-998-0193-y

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