THE EFFECT OF DIETARY SUPPLEMENTATION WITH n - 3 POLYUNSATURATED FATTY ACIDS ON THE SYNTHESIS OF INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR BY MONONUCLEAR CELLS

We examined whether the synthesis of inter­ leukin-1 or tumor necrosis factor, two cytokines with po­ tent inflammatory activities, is influenced by dietary sup­ plementation with n -3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concen­ trate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1/3 and IL-1 a) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1/3 was suppressed from 7.4±0.9 ng per milliliter at base line to 4.2±0.5 ng per milliliter after six weeks of supplementa­ tion (43 percent decrease; P = 0.048). Ten weeks after the end of n -3 supplementation, we observed a further decrease to 2.9±0.5 ng per milliliter (61 percent decrease; IN T E R L E U K IN 1 and tumor necrosis factor are polypeptide cytokines synthesized by monocytes and other cells in response to injury, as well as to infectious, inflammatory, or immunologic chal­ lenges. 1' 3 These cytokines induce local inflammatory changes and mediate several systemic acute-phase re­ sponses.4,3 Moreover, interleukin-1 and tumor necro­ sis factor often act synergistically — e.g., on vascular endothelium ,'1 insulin production ,7 and the synthesis of metabolites of arachidonic acid .8 The n —3 (also called omega-3) fatty acids are polyFrom the Department of Medicine, New England Medical Center Hospi­ tals and Tufts University School of Medicine (S .E.. R .G ., K .G ., G .L ., J .W .M .vdM ., J .G .C ., M .S .K ., S .M .W ., C .A .D .) , the Department of Medicine. Brigham and W omen’s Hospital and Harvard Medical School (V .E .K ., T .S .R .), and the U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (E .J.S .), Boston; and the Institut für Prophylaxe der Kreislaufkrankheiten und Medizinische Klinik Innenstadt, Universität München, Munich, Federal Republic of Germany (P .C .W .). Address reprint requests to Dr. Dinarello at the Division of Geographic Medicine and Infectious Diseases, De­ partment of Medicine, Tufts-New England Medical Center, 750 Washington St., Boston, M A 02111. Supported by grants (AI-15614, AM-36149, RR-00054, and HL-35243) from the National Institutes of Health and under a contract (53-3K06-5-10) with the U.S. Department of Agriculture Research. Dr. Endres is the recipient of a grant from the Deutsche Forschungsgemeinschaft. Presented in part at the International Workshop on Monokines and Other Nonlymphocytic Cytokines, Hilton Head, S .C ., December 1987, and published in abstract form (J Leukocyte Biol 1987; 42:617). P = 0.005). The production of IL-1 a and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 /3, IL-1 a, and tumor necrosis factor had returned to the presupple­ ment level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1/3, IL-1 a, and tu­ mor necrosis factor can be suppressed by dietary supple­ mentation with long-chain n -3 fatty acids. The reported antiinflammatory effect of these n -3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor. (N Engl J Med 1989; 320:265-71.) unsaturated fatty acids in which the last double bond is located between the third and fourth carbon atom from the methyl end of the fatty acid chain. These fatty acids are scarce in a normal Western diet but make up an appreciable part of the fat intake in diets rich in cold-water fish and seal meat.'' Epidemiologic studies in populations of coastal Eskimo,10,1! Jap a ­ nese,1“ and D utch 1 * subjects have shown that a high intake of n — 3 fatty acids correlates with a low inci­ dence of cardiovascular and inflammatory diseases such as asthma and Type I diabetes mellitus. 11 The modification of the fatty acid composition of cell membranes and the formation of eicosanoids by di­ etary supplementation with n — 3 fatty acids have sub­ sequently been shown in hum an beings . 14,10 In healthy volunteerslb and in patients with asthma , 17 n —3 dietary supplementation results in decreased neutrophil chemotaxis and inhibited generation of leukotriene B4 by neutrophils and monocytes. In clini­ cal studies, dietary supplementation with n —3 fatty acids has led to improvements in patients with rheu­ matoid arthritis18 and in patients with psoriasis. 14 Prospective studies in animals fed n —3 fatty acids sup­ port these clinical observations.20'23 Since interleukin1 and tumor necrosis factor are the principal polypeptide mediators of inflammation, 266 THE NEW ENGLAND JOURNAL OF MEDICINE Feb. 2, 1989 reduced production of these cytokines may contribute to the amelioration of inflammatory symptoms in pa­ tients receiving n — 3 supplementation. In this study we investigated the effects of dietary supplementa­ tion with n — 3 fatty acids on the synthesis of the cyto­ kines interleukin1 and tumor necrosis factor in nor­ mal subjects.