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Dietary fish oil n−3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation

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Lipids

Abstract

The higher incidence of inflammatory diseases in Western countries might be related, in part, to a high consumption of saturated fatty acids and n−6 polyunsaturated fatty acids (PUFA) and an insufficient intake of n−3 fatty acids. The purpose of this study was to examine the effects of dietary n−3 fatty acids on innate and specific immune response and their anti-inflammatory action in models of contact and atopic dermatitis. Balb/C mice were fed for 3 wk either n−6 or n−3 PUFA-fortified diets. After inducing a contact or an atopic dermatitis, immunological parameters were analyzed to evaluate the anti-inflammatory potential of these n−3 PUFA. n−3 PUFA reduced innate and specific immune responses through inhibition of TH1 and TH2 responses, increase of immunomodulatory cytokines such as IL-10, and regulation of gene expression. The inhibition of both kinds of responses was confirmed by the anti-inflammatory effect observed in contact and atopic dermatitis. Reduction in weight, edema, thickness, leukocyte infiltration, and enhancement of antioxidant defenses in the inflamed ears of mice from both models along with the prevention of delayed-type hypersensitivity induced in atopic dermatitis proved n−3 PUFA efficacy. Our data suggest that dietary fish oil-derived n−3 fatty acids have immunomodulatory effects and could be useful in inflammatory disorders.

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Abbreviations

ARA:

arachidonic acid

Con A:

concanavalin A

COX:

cyclooxygenase

DNFB:

2,4-dinitro-1-fluorobenzene

DTH:

delayed-type hypersensitivity

FO:

fish oil

GSH:

glutathione

LOX:

lipooxygenase

LPS:

lipopolysacharide

LXB:

liver X receptor

M-CSF:

macrophage-colony stimulating factor

MDA:

malondialdehyde

MPO:

mieloperoxidase

PGE2 :

prostaglandin E2

PPAR:

peroxisome proliferator-activated receptor

SO:

sunflower oil

References

  1. Harbige, L.S. (2003) Fatty Acids, the Immune Response, and Autoimmunity: A Question of n−6 Essentiality and the Balance Between n−6 and n−3. Lipids 38, 323–341.

    Article  PubMed  CAS  Google Scholar 

  2. Morris, M. (1997) Nutritional Modification of Inflammatory Diseases, Semin. Vet. Med. Surg., 12, 212–222.

    Article  Google Scholar 

  3. Kelley, D.S. (2001) Modulation of Human Immune and Inflammatory Responses by Dietary Fatty Acids, Nutrition 17, 669–673.

    Article  PubMed  CAS  Google Scholar 

  4. Calder, P.C. (2003) N−3 Polyunsaturated Fatty Acids and Inflammation: From Molecular Biology to the Clinic, Lipids 38, 343–352.

    Article  PubMed  CAS  Google Scholar 

  5. Prescott, S.L., and Calder, P.C. (2004) N−3 Polyunsaturated Fatty Acids and Allergic Disease, Curr. Opin. Clin. Nutr. Metab. Care 7, 123–129.

    Article  PubMed  CAS  Google Scholar 

  6. Cordain, L., Eaton, S.B., Sebastian, A., Mann, N., Lindeberg, S., Watkins, G.A., O'Keefe, J.H., and Brand-Miller, J. (2005) Origin and Evolution of the Western Diet: Health Implications for the 21st Century, Am. J. Clin. Nutr. 81, 341–354.

    PubMed  CAS  Google Scholar 

  7. Wahle, K.H., Caruso, D., Ochoa, J.J., and Quiles, J.L. (2004) Olive Oil and Modulation of Cell Signaling in Disease Prevention. Lipids 29, 1223–1231.

    Article  Google Scholar 

  8. Simopoulus, A.P. (2002) Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases. J. Am. Coll. Nutr., 21, 695–505.

    Google Scholar 

  9. Camuesco, D., Galvez, J., Nieto, A., Comalada, M., Rodriguez-Cabezas, M.E., Concha, A., Xaus, J., and Zarzuelo, A. (2005) Dietary Olive Oil Supplemented with Fish Oil, Rich in EPA and DHA (n−3) Polyunsaturated Fatty Acids, Attenuates Colonic Inflammation in Rats with DSS-Induced Colitis, J. Nutr. 135, 687–694.

    PubMed  CAS  Google Scholar 

  10. Kremer, J.M. (2000) Fatty Acids Supplementation in Rheumatoid Arthritis. Am. J. Clin. Nutr. 71, 349S-351S.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Remants, P.H., Sont, J.K., Wagenaar, L.W., Wouters-Wesseling, W., Zuijderduin, W.M., Jongma, A., Breedveld, F.C., and Van Laar, J.M. (2004) Nutrients Supplementation with Polyunsaturated Fatty Acids and Micronutrients in Rheumatoid Arthritis: Clinical and Biochemical Effects, Eur J. Clin. Nutr., 58, 839–845.

    Article  CAS  Google Scholar 

  13. McLean, C.H., Mojica, W.A., Newberry, S.J., Pencharz, J., Garland, R.H., Tu, W., Hilton, L.G., Gralnek, I.M., Rhodes, S., Khanna, P., and Morton, S.C. (2005) Systematic Review of the Effect of n−3 Fatty Acids in Inflammatory Bowel Disease. Am. J. Clin. Nutr. 82, 611–619.

    Google Scholar 

  14. Calder, P.C. (1998) Fat Chance of Immunomodulation. Trends Immunol. 19, 244–247.

    CAS  Google Scholar 

  15. Calder, P.C., Yaqoob, P., Thies, F., Wallace, F.A., and Miles, E.A. (2002) Fatty Acids and Lymphocyte Functions, Br. J. Nutr. 87 (Suppl. 1), S31-S48.

    Article  PubMed  CAS  Google Scholar 

  16. De Pablo, M.A., and Álvarez de Cienfuegos, G. (2000) Modulatory Effects of Dietary Lipids on Immune System Functions, Immunol. Cell Biol., 78, 31–39.

    Article  PubMed  Google Scholar 

  17. Calder, P.C. (2005) Polyunsaturated Fatty Acids and Inflammation, Biochem. Soc. Trans. 33, 423–427.

    Article  PubMed  CAS  Google Scholar 

  18. Institute of Laboratory Animal Resource Commission of Life Sciences. (1996) National Research Council, in: Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.

    Google Scholar 

  19. Lepage, G., and Roy, C.C. (1986) Direct Transesterification of All Classes of Lipids in One Step Reaction. J. Lipid. Res. 27, 114–120.

    PubMed  CAS  Google Scholar 

  20. Kelley, D.S., Warren, J.M., Simon, V.A., Bartolini, G., Mackey, B.E., and Erickson, K.L. (2002) Similar effects of c9,t11-CLA and c10, t12-CLA on Immune Cells Functions in Mice, Lipids 37, 725–728.

    Article  PubMed  CAS  Google Scholar 

  21. Comalada, M., Xaus, J., Sánchez, E., Valledor, A.F., and Celada, A. (2004) Macrophage Colony-Stimulating Factor-, Granulocyte-Macrophage Colony-Stimulating Factor-, or IL-3-Dependent Survival of Macrophages, But Not Proliferation, Requires the Expression of p21waf1 Through the Phosphatidylinositol 3-Kinase/Akt Pathway, Eur. J. Immunol., 34, 2257–2267.

    Article  PubMed  CAS  Google Scholar 

  22. Celada, A., Gray, P.W., Rinderknecht, E., and Schreiber, R.D. (1984) Evidence for Gamma-Interferon Receptor that Regulates Macrophage Tumoricidal Activity, J. Exp. Med. 160, 55–74.

    Article  PubMed  CAS  Google Scholar 

  23. Celada, A., Borras, F., Soler, C., Lloberas, J., Klemsz, M., van Beveren, C., McKercher, S., and Maki, R.A. (1996) The Transcription Factor PU.1 Is Involved in Macrophage Proliferation, J. Exp. Med. 184, 61–69.

    Article  PubMed  CAS  Google Scholar 

  24. Xuas, J., Valledor, A.F., Cardó, M., Marques, L., Beleta, J., Palacios, J.M., and Celada, A. (1999) Adenosine Inhibits Macrophage Colony-Stimulating Factor-Dependent Proliferation of Macrophage Through the Induction of p27Klp1 Expression. J. Immunol., 113, 337–348.

    Google Scholar 

  25. Sierra, S., Lara-Villoslada, F., Olivares, M., Jiménez, J., Boza, J., and Xaus, J. (2005) Increased Immune Response in Mice Consuming Rice Bran Oil, Eur. J. Nutr. 44, 509–516.

    Article  PubMed  CAS  Google Scholar 

  26. Fukunaga, K., Yoshida, M., and Nakazono, N. (1998) A Simple, Rapid, High Sensitive and Reproducible Method Quantification for Plasma Malondialdehyde by High Performance Liquid Chromatography, Biomed. Chromatograph. 12, 300–303.

    Article  CAS  Google Scholar 

  27. Tomobe, Y.I., Morizawa, K., Tsuchida, M., Hibino, H., Nakano, I., and Tanaka, Y. (2000) Dietary Docohexaenoic Acid Supp-presses Inflammation and Immunoresponses in Contact Hypersensitivity Reaction in Mice, Lipids 35, 61–69.

    Article  PubMed  CAS  Google Scholar 

  28. Piltz, T., Saint-Mézard, P., Satho, M., Herren, S., Waltzinger, C., Bittencourt, M.C., Kosco-Vilbois, M.H., and Chvatchko, Y. (2003) IL-18 Binding Protein Protects Against Contact Hypersensitivity, J Immunol. 171, 1164–1171.

    Google Scholar 

  29. Perán, L., Camuesco, D.D., Comalada, M., Nieto, A., Concha, A., Diaz-Ropero, M.P., Olivares, M., Xaus, J., Zarzuelo, A., and Galvez, J. (2005) Preventative Effects of a Probiotic, Lactobacillus salivarius, in the TNBS Model of Rat Colitis, World J. Gastroenterol. 11, 5185–5192.

    PubMed  Google Scholar 

  30. Leung, D.Y.M., Boguniwicz, M., Howeel, M.D., Nomura, I., and Hamid, Q.A. (2004) New Insights into Atopic Dermatitis, J. Clin. Invest. 113, 651–657.

    Article  PubMed  CAS  Google Scholar 

  31. Harris, W.S. (1989) Fish Oils and Plasma Lipid and Lipoprotein Metabolism in Humans: A Critical Review, J. Lipid Res. 30, 785–807.

    PubMed  CAS  Google Scholar 

  32. Bonna, K.H., Bjerve, K.S., Straume, B., Gram, I.T., and Thelle, D. (1990) Effects of Eicopentaenoic and Docohexaenoic Acids on Blood Pressure in Hypertension. A Population-Based Intervention Trial from the Tromso Study. N. Engl. J. Med. 322, 795–801.

    Article  Google Scholar 

  33. Beck, S.A., Smith, K.L., and Tisdale, M.J. (1991) Anticachectic and Antitumor Effect of Eicosapentaenoic Acid and Its Effect on Protein Turnover, Cancer Res., 51, 6089–6093.

    PubMed  CAS  Google Scholar 

  34. Robinson, D.R., Xu, L.L., Tateno, S., Guo, M., and Colvin, R.B. (1993) Suppression of Autoimmune Disease by Dietary n−3 Fatty Acids, J. Lipid. Res. 34, 1435–1444.

    PubMed  CAS  Google Scholar 

  35. Peterson, L.D., Thies, F., Sanderson, P., Newsholme, E.A., and Calder, P.C. (1998) Eicosapentaenoic and Docosahexaenoic Acids Mimic the Effect of Fish Oil upon Rat Lymphocytes. Life Sci. 62, 2209–2017.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  37. Puertollano, M.A., de Pablo, M., and Alvarez de Cienfuegos, G. (2003) Anti-Oxidant Properties of N-Acetyl-Cysteine Do Not Improve the Immune Resistance of Mice Fed Dietary Lipids to Listeria monocytogenes Infection, Clin. Nutr. 22, 313–319.

    Article  PubMed  CAS  Google Scholar 

  38. Ly, L.H., Smith III, R., Chapkin, R.S., and McMurray, D.N. (2004) Dietary n−3 Polyunsaturated Fatty Acids Suppress Splenic CD4+ T Cell Function in Interleukin 10-/-. Clin. Exp. Immunol. 139, 202–209.

    Article  CAS  Google Scholar 

  39. Kasim-Karakas, S.E. (1995) Impact of n−3 Fatty Acids on Lipoprotein Metabolism, Curr. Opin. Lipidol. 6, 167–171.

    Article  PubMed  CAS  Google Scholar 

  40. Stolina, M., Sharma, S., Lin, Y., Dahadwala, M., Gardner, B., Luo, J., Zhu, L., Kronenberg, M., Miller, P.W., and Portanova, J. (2000) Specific Inhibition of Cyclooxigenase 2 Restores Antitumor Reactivity by Altering the Balance of IL-10 and IL-12 Synthesis. J. Immunol. 164, 361–370.

    PubMed  CAS  Google Scholar 

  41. Antoniv, T.T., Park-Min, K.H., and Ivashkiv, L.B. (2005) Kinetics of IL-10-Induced Gene Expression in Human Macrophages. Immunobiology, 210, 87–95.

    Article  PubMed  CAS  Google Scholar 

  42. Loscher, C.E., Draper, E., Leavy, O., Kelleher, D., Mills, K.H., and Roche, H.M. (2005) Conjugated Linoleic Acid Suppress NF-Kappa B Activation and IL-12 Production in Dendritic Cells Through ERK-Mediated IL-10 Induction, J. Immunol. 175, 4990–4998.

    PubMed  CAS  Google Scholar 

  43. Joseph, S.B., Castrillo, A., Laffitte, B.A., Mangelsdorf, D.J., and Tontonoz, P. (2003) Reciprocal Regulation of Inflammation and Lipid Metabolism by Liver X Receptors, Nat. Med. 9, 213–219.

    Article  PubMed  CAS  Google Scholar 

  44. Kim, S.R., Lee, K.S., Park, H.S., Park, S.J., Min, K.H., Jin, S.M., and Lee, Y.C. (2005) Involvement of IL-10 in Peroxisome Proliferators-Activated Receptor Gamma-Mediated Anti-Inflammatory Response in Asthma, Mol. Pharmacol. 68, 1568–1575.

    PubMed  CAS  Google Scholar 

  45. Li, H., Ruan, X.Z., Fernando, R., Mon, W.Y., Wheeler, D.C., Moorhead, J.F., and Verghese, Z. (2005) EPA and DHA Reduce LPA-Induced Inflammation Responses in HK-2 Cells: Evidence for a PPAR-Gamma-Dependent Mechanism. Kidney Int., 67, 867–874.

    Article  PubMed  CAS  Google Scholar 

  46. Hyun, E., Bolla, M., Steinhoff, M., Wallace, J.L., Soldato, P., and Vergnolle, N. (2004) Anti-Inflammatory Effects of Nitric Oxide-Releasing Hydrocortisone NCX 1022, in a Murine Model of Contact Dermatitis, Br. J. Pharmacol. 143, 618–625.

    Article  PubMed  CAS  Google Scholar 

  47. Camuesco, D., Comalada, M., Concha, A., Nieto, A., Sierra, S., Xaus, J., Zarzuelo, A., and Galvez J., (2005) Intestinal Anti-inflammatory Activity of Combined Quercitrin and Dietary Olive Oil Supplemented with Fish Oil Rich in EPA and DHA (n−3) Polyunsaturated Fatty Acids in Rats with DSS-Induced Colitis, Clin. Nutr. 25, 466–476.

    Article  CAS  Google Scholar 

  48. Barbosa, D.S., Cecchini, R., El Kadri, M.Z., Rodriguez, M.A., Burini, R.C., and Dichi, I. (2003) Decreased Oxidative Stress in Patients with Ulcerative Colitis Supplemented with Fish Oil Omega-3 Fatty Acids, Nutrition, 19, 387–342.

    Google Scholar 

  49. Ishihara, K., Oyamada, C., Matsushima, R., Murata, M. and Muraoka, T. (2005) Inhibitory Effect of Porphyran, Prepared from Dried “Nori”, on Contact Hypersensitivity in Mice, Biosci. Biotechnol. Biochem., 69, 1824–1830.

    Article  PubMed  CAS  Google Scholar 

  50. Kakae, S., Naruse-Nakajima, C., Sudo, K., Horai, R., Asano, M., and Iwakura, Y. (2001) Il-1α But Not IL-1β, Is Required for Contact-Allergen-Specific T Cell Activation During the Sensitization Phase in Contact Hypersensitivity, Int. Immunol. 13, 1471–1478.

    Article  Google Scholar 

  51. Hayashi, N., Tashiro, T., Yamamori, H., Takagi, K., Morishima, Y., Otsubo, Y., Sugiera, T., Furukawa, K., Nitta, H., Nakajima, N., Suzuki, N. and Ito, I. (1998) Effects of Intravenous Omega-3 and Omega-6 Fat Emulsion on Cytokine Production and Delayed Type Hypersensitivity in Burned Rats Receiving Total Parenteral Nutrition. J. Parenter. Enteral Nutr. 22, 363–367.

    Article  CAS  Google Scholar 

  52. Hoff, S., Seiler, H., Heinrich, J., Hompauer, I., Nieters, A., Becker, N., Nagel, G., Gedrich, K., Karg, G., Wolfram, G., and Linseisein, J. (2005) Allergic Sensitization and Allergic Rhinitis Are Associated with n−3 Polyunsaturated Fatty Acids in the Diet and in Red Blood Cell Membranes, Eur. J. Clin. Nutr., 59, 1071–1080.

    Article  PubMed  CAS  Google Scholar 

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Sierra, S., Lara-Villoslada, F., Comalada, M. et al. 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 (2006). https://doi.org/10.1007/s11745-006-5061-2

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