Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men†
Corresponding Author
D. S. Kelley
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
To whom correspondence should be addressed at USDA, ARS, Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, CA 94129. E-mail: [email protected]Search for more papers by this authorP. C. Taylor
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
Search for more papers by this authorG. J. Nelson
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
Search for more papers by this authorPerla C. Schmidt
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
Search for more papers by this authorAldo Ferretti
Beltsville Human Nutrition Center, Beltsville, Maryland
Search for more papers by this authorB. E. Mackey
Western Regional Research Center, Albany, California
Search for more papers by this authorCorresponding Author
D. S. Kelley
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
To whom correspondence should be addressed at USDA, ARS, Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, CA 94129. E-mail: [email protected]Search for more papers by this authorP. C. Taylor
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
Search for more papers by this authorG. J. Nelson
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
Search for more papers by this authorPerla C. Schmidt
Western Human Nutrition Research Center, USDA, ARS, P.O. Box 29997, Presidio of San Francisco, CA, 94129
Search for more papers by this authorAldo Ferretti
Beltsville Human Nutrition Center, Beltsville, Maryland
Search for more papers by this authorB. E. Mackey
Western Regional Research Center, Albany, California
Search for more papers by this authorParts of data included here were published in abstracts for the Experimental Biology 98, and the International Congress of Immunology 98, meetings.
Abstract
The purpose of this study was to examine the effects of feeding docosahexaenoic acid (DHA) as triacylglycerol on the fatty acid composition, eicosanoid production, and select activities of human peripheral blood mononuclear cells (PBMNC). A 120-d study with 11 healthy men was conducted at the Metabolic Research Unit of Western Human Nutrition Reach Center. Four subjects (control group) were fed the stabilization diet throughout the study; the remaining seven subjects were fed the basal diet for the first 30 d, followed by 6 g DHA/d for the next 90 d. DHA replaced an equivalent amount of linoleic acid; the two diets were comparable in their total fat and all other nutrients. Both diets were supplemented with 20 mg d α-tocopherol acetate per day. PBMNC fatty acid composition and eicosanoid production were examined on day 30 and 113; immune cell functions were tested on day 22, 30, 78, 85, 106, and 113. DHA feeding increased its concentration from 2.3 to 7.4 wt% in the PBMNC total lipids, and decreased arachidonic acid concentration from 19.8 to 10.7 wt%. It also lowered prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, in response to lipopolysaccharide, by 60–75%. Natural killer cell activity and in vitro secretion of interleukin-1β and tumor necrosis factor α were significantly reduced by DHA feeding. These parameters remained unchanged in the subjects fed the control diet. B-cell functions as reported here and T-cell functions that we reported previously were not altered by DHA feeding. Our results show that inhibitory effects of DHA on immune cell functions varied with the cell type, and that the inhibitory effects are not mediated through increased production of PGE2 and LTB4.
REFERENCES
- 11. H.O., Dyerberg, J., and Horn, N. (1976) The Composition of Foods Consumed by Greenland Eskimos, Acta Med. Scand. 200, 69–73.
- 22. Kelley, D.S., Branch, L.B., Love, J.E., Taylor, P.C., Rivera, Y.M., and Iacono, J.M. (1991) Dietary α-Linolenic Acid and Immunocompetence in Humans, Am. J. Clin. Nutr. 53, 40–46.
- 33. Hughes, D.A., Pinder, A.C., Piper, Z., Johnson, I.T., and Lund, E.K. (1996) Fish Oil Supplementation Inhibits the Expression of Major Histocompatibility Complex Class II Molecules and Adhesion Molecules on Human Monocytes, Am. J. Clin. Nutr. 63, 267–272.
- 44. Bjerve, K.S., Fischer, S., Wammer, F., and England, T. (1989) α-Linolenic Acid and Long-Chain ω-3 Fatty Acid Supplementation in Three Patients with ω-3 Fatty Acid Deficiency, Am. J. Clin. Nutr. 49, 290–300.
- 55. Caughey, G., Montzioris, E., Gibson, R.A., Cleland, L.G., and James, M.J. (1996) The Effect on Human Tumor Necrosis Factor a and Interleukin 1β Production of Diets Enriched in n-3 Fatty Acids from Vegetable Oil or from Fish Oil, Am. J. Clin. Nutr. 63, 116–122.
- 66. Endres, S., Ghorbani, R., Kelley, V.E., Georgilis, K., Lonnemann, G., Van der Meer, J.W.M., Cannon, J.G., Rogers, T.S., Klempner, M.S., Weber, P.C., Schaefer, E.J., Schaefer, S.M., and Dinarello, C.A. (1989) The Effect of Dietary Supplementation with n-3 Polyunsaturated Fatty Acids on the Synthesis of Interleukin-1 and Tumor Necrosis Factor by Mononuclear Cells, New Engl. J. Med. 320, 265–271.
- 77. Endres, S., Meydeni, 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.
- 88. Lee, T.H., Hoover, R.L., Williams, J.D., Sperling, R.I., Ravalese, J., Spur, B.W., Robinson, D.R., Corey, E.J., Lewis, R.A., and Austen, K.F. (1985) Effect of Dietary Enrichment with Eicosapentaenoic Acid and Docosahexaenoic Acids on in vitro Neutrophil and Monocyte Leukotriene Generation and Neutrophil Function, New Engl. J. Med. 312, 1217–1224.
- 99. Payan, D.G., Wong, M.Y.S., Chernov-Rogan, T., Valone, F.H., Pickett, W.C., Blake, V., and Gold, W.M. (1986) Alteration in Human Leukocyte Function Induced by Ingestion of Eicosapentaenoic Acid, J. Clin. Immunol. 6, 402–410.
- 1010. Virella, G., Kilpatrick, J.M., Rugeles, M.R., Hayman, B., and Russel, R. (1989) Depression of Humoral Responses and Phagocytic Functions in vivo and in vitro by Fish Oil and Eicosapentaenoic acid, Clin. Immunol. Immunopath. 52, 257–270.
- 1111. Kramer, T.R., Schoene, N., Douglass, L.W., Judd, J.W., Ballard-Barbash, J.T., Taylor, R., Bhagavan, P.R., and Nair, P.P. (1991) Increased Vitamin E Intake Restores Fish Oil-Induced Suppressed Blastogenesis of Mitogen-Stimulated T Lymphocytes, Am. J. Clin. Nutr. 54, 896–902.
- 1212. Molvig, J., Pociot, F., Worssaae, H., Wogensen, L.D., Baek, L., Christensen, P., Mandrup-Poulsen, T., Anderson, K., Madsen, P., Dyerberg, J., and Nerup, J. (1991) Dietary Supplementation with ω-3-Polyunsaturated Fatty Acids Decreases Mononuclear Cell Proliferation and Interleukin-1β Content but not Monokine Secretion in Healthy and Insulin-Dependent Diabetic Individuals, Scand. J. Immunol. 34, 399–410.
- 1313. 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.
- 1414. Wallace, J.M.W., Turley, E., Gilmore, W.S., and Strain, J.J. (1995) Dietary Fish Oil Supplementation Alters Leukocyte Function and Cytokine Production in Healthy Women, Arterioscler. Thromb. Vasc. Biol. 15, 185–189.
- 1515. Yamashita, N., Maruyama, M., Yamazaki, K., Hamazaki, T., and Yano, S. (1991) Effect of Eicosapentaenoic Acid and Docosahexaenoic Acid on Natural Killer Cell Activity in Human Peripheral Blood Lymphocytes, Clin. Immunol. Immunopath. 59, 335–345.
- 1616. 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.
- 1717. Kelley, D.S., Branch, L.B., and Iacono, J.M. (1989) Nutritional Modulation of Human Immune Status, Nutr. Res. 9, 965–975.
- 1818. Kelley, D.S., Dougherty, R.M., Branch, L.B., Taylor, P.C., and Iacono, J.M. (1992) Concentration of Dietary n-6 Polyunsaturated Fatty Acids and Human Immune Status, Clin. Immunol. Immunopath. 62, 240–244.
- 1919. Barone, J., Hebert, J.R., and Reddy, M.M. (1989) Dietary Fat and Natural Killer Cell Activity, Am. J. Clin. Nutr. 50, 861–867.
- 2020. Khalfoun, B., Thibault, G., Lacord, M., Bardos, P., and Lebranchu, Y. (1996) Docosahexaenoic and Eicosapentaenoic Acids Inhibit Human Lymphoproliferative Responses in vitro but Not the Expression of T Cell Surface Markers, Scand. J. Immunol. 43, 248–256.
- 2121. Lim, B.O., Yamada, K., Hung, P., Watanabe, T., Taniguchi, S., and Sugano, M. (1996) Effects of n-3 Polyunsaturated Fatty Acids and Lectins on Immunoglobulin Production by Spleen Lymphocytes of Sprague-Dawley Rats, Biosci. Biotechnol. Biochem. 60, 1025–1027.
- 2222. Jolly, C., Jiang, Y.H., Chapkin, R.S., and McMurray, D. (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.
- 2323. Bechoua, S., Dubois, M., Nemoz, G., Lagarde, M., and Prigent, A.-F. (1998) Docosahexaenoic Acid Lowers Phosphatidate Level in Human Activated Lymphocyte Despite Phospholipase D Activation, J. Lipid Res. 39, 873–883.
- 2424. Kinsella, J.E., Lokesh, B., Broughton, S., and Whelan, J. (1990) Dietary Polyunsaturated Fatty Acids and Eicosanoids. Potential Effects on the Modulation of the Inflammatory and Immune Cells: An Overview, Nutrition 6, 24–44.
- 2525. U.S. Department of Agriculture, Composition of Foods, U.S. Government Printing Office, Washington, DC, 1987. [Revised Agriculture Handbook no. 8.1–8.14.]
- 2626. 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.
- 2727. Hierholzer, J.C., Suggs, M.T., and Hall, E.C. (1969) Standardized Viral Hemagglutination and Hemagglutination Tests. II. Description and Statistical Evaluation, App. Microbiol. 18, 824–833.
- 2828. Nelson, G.J. (1972) Handling, Extraction and Storage of Blood Samples, in Blood Lipids and Lipoproteins ( G.J. Nelson, ed.) Wiley-Interscience, New York, pp. 3–24.
- 2929. Nelson, G.J. (1975) Quantitative Analytical Methods for Blood Lipids, in Analysis of Lipids and Lipoproteins ( E.G. Perkins, ed.) American Oil Chemists' Society, Champaign, pp. 1–22.
- 3030. Nelson, G.J., Kelley, D.S., and Hunt, J.E. (1986) Effect of Nutritional Status on the Fatty Acid Composition of Rat Liver and Cultured Hepatocytes, Lipids 21, 454–459.
- 3131. Nelson, G.J., Kelley, D.S., Schmidt, P.C., and Serrato, C.M. (1987) The Effect of Fat-Free, Saturated and Polyunsaturated Fat Diets on Rat Liver and Plasma, Lipids 22, 88–94.
- 3232. Littell, R.C., Milliken, G.A., Stroup, W.W., Wolfinger, R.D. (1996) SAS$TM System for Mixed Models, SAS Institute Inc., Cary, p. 633.
- 3333. Kelley, D.S., Taylor, P.C., Nelson, G.J., and Mackey, B.E. (1998) Dietary Docosahexaenoic Acid and Immunocompetence in Young Healthy Men, Lipids 33, 559–566.
- 3434. Conquer, J.A., and Holub, B.J. (1997) Dietary Docosahexaenoic Acid as a Source of Eicosapentaenoic Acid in Vegetarians and Omnivores, Lipids 32, 341–345.
- 3535. Brossard, N., Crosset, M., Pachiudi, C., Riou, J.P., and Tayot, J.L. (1996) Retroconversion and Metabolism of 13 C, 22:6n-3 in Humans and Rats After Intake of a Single Dose of 13 C, 22:6n-3-Triacylglycerols, Am. J. Clin. Nutr. 64, 577–586.
- 3636. Nelson, G.J., Schmidt, P.C., Bartolini, G.L., Kelley, D.S., and Kyle, D. (1997) The Effect of Dietary Docosahexaenoic Acid on Plasma Lipoproteins and Tissue Fatty Acid Composition in Humans, Lipids 32, 1137–1146.
- 3737. Joulain, C., Guichardant, M., Lagarde, M., and Prigent, A.F. (1995) Influence of Polyunsaturated Fatty Acids on Lipid Metabolism in Human Mononuclear Cells and Early Biochemical Events Associated with Lymphocyte Activation, J. Lipid Mediat. Cell Signal 11, 63–79.
- 3838. Rotondo, D., Earl, C.R., Laing, K.J., and Kaimakamis, D. (1994) Inhibition of Cytokine-Stimulated Thymic Lymphocyte Proliferation by Fatty Acids: The Role of Eicosanoids, Biochim. Biophys. Acta 1223, 185–194.
- 3939. Santoli, D., Phillips, P.D., Colt, T.L., and Zurier, R.B. (1990) Suppression of IL 2-Dependent Cell Growth in vitro by Prostaglandin E (PGE) and Their Precursor Fatty Acids. Evidence for a PGE-Independent Mechanism of Inhibition by the Fatty Acids, J. Clin. Invest. 85, 424–432.
- 4040. 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.
- 4141. Ceuppens, J.L., and Desmyter, J. (1987) Effect of Prostaglandin Synthesis Inhibition in vivo on the Immune Response Following Hepatitis B Vaccination in Normal Subjects, Intl. J. Immunopharmacol. 9, 803–810.
- 4242. Rola-Pleszczynski, M.I., and Lemaire, I. (1985) Leukotrienes Augment Interleukin 1 Production by Human Monocytes, J. Immunol. 135, 3958–3963.
- 4343. Rola-Pleszczynski, M., Gagnon, L., and Chavaellaz, P.-A. (1988) Immune Regulation by Leukotriene B4, Ann. N.Y. Acad. Sci. 524, 218–225.
- 4444. Shapiro, A.C., Wu, D., and Meydani, S.N. (1993) Eicosanoids Derived from Arachidonic and Eicosapentaenoic Acids Inhibit T Cell Proliferative Response, Prostaglandins 45, 229–240.
- 4545. Curtis, L.K. (1992) Cholesterol, Apolipoprotein E, and Immune Cell Function, in Nutrient Modulation of the Immune Response ( Cunningham-Rundles, Susanna, ed.) Marcel Dekker, Inc., New York, pp. 169–181.
