Omega-3 fatty acid uses

Omega-3 fattyacids which possess the most potent immunomodulatoryactivities, and among the omega-3 those from fish oil—eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA)—are more biologicallypotent than

-linolenic acid (ALA). Some of the effects of omega-3 are brought about by modulation of the amount and typesof eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways,transcription factor activity and gene expression. Animal experimentsand clinical intervention studies indicate that omega-3 fattyacids have anti-inflammatory properties and, therefore, mightbe useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer arecharacterized by an increased level of interleukin 1 (IL-1),a proinflammatory cytokine. Similarly, arthritis, Crohn’sdisease, ulcerative colitis and lupus erythematosis are autoimmunediseases characterized by a high level of IL-1 and the proinflammatoryleukotriene LTB₄ produced by omega-6 fatty acids. There havebeen a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmunediseases in humans, including rheumatoid arthritis, Crohn’sdisease, ulcerative colitis, psoriasis, lupus erythematosus,multiple sclerosis and migraine headaches. Many of the placebo-controlledtrials of fish oil in chronic inflammatory diseases reveal significantbenefit, including decreased disease activity and a lowereduse of anti-inflammatory drugs.

Key words: inflammation, cardiovascular disease and major depression autoimmune diseases, IL-1, IL-6, TNF, background diet, omega-6/omega-3 ratio

Key teaching points:

• In Western diets, omega-6 fatty acids are the predominantpolyunsaturated fats. The omega-6 and omega-3 fatty acids aremetabolically distinct and have opposing physiologic functions.

• Eicosapentaenoic acid (EPA) is released to compete witharachidonic acid (AA) for enzymatic metabolism inducing theproduction of less inflammatory and chemotactic derivatives.

• Animal and human studies support the hypothesis that omega-3 PUFA suppress cell mediated immune responses.

• In experimental animals and humans, serum PUFA levelspredict the response of proinflammatory cytokines to psychologicstress. Imbalance in the omega-6/omega-3 PUFA ratio in majordepression may be related to the increased production of proinflammatorycytokines and eicosanoids in that illness.

• The increased omega-6/omega-3 ratio in Western diets most likely contributes to an increased incidence of cardiovasculardisease and inflammatory disorders.

• Patients with autoimmune diseases, such as rheumatoidarthritis, inflammatory bowel disease and asthma, usually respondto eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)supplementation by decreasing the elevated levels of cytokines.

	Introduction

The first evidence of the important role of dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) in inflammation was derived from epidemiological observations of the low incidence of autoimmune and inflammatory disorders, such as psoriasis, asthma and type-1 diabetes, as well as the complete absence of multiple sclerosis, in a population of Greenland Eskimos compared with gender- and age-matched groups living in Denmark [1]. Most of these diseases are characterized by inappropriate activation of T cells resulting on and ultimately destruction of host tissues.
In the 1980’s several independent lines of evidence suggested that changes in the natural history of hypertensive, atherosclerotic and chronic inflammatory disorders may be achieved by altering availability of eicosanoid precursors. Native Greenland Eskimos [2] and Japanese [3] have a high dietary intake of long chain omega-3 PUFA from seafood and a low incidence of myocardial infarction and chronic inflammatory or autoimmune disorders, even when compared to their Westernized ethnic counterparts. Diets containing omega-3 PUFA have also been found to reduce the severity of experimental cerebral [4] and myocardial [5] infarction, to retard autoimmune nephritis and prolong survival of NZB x NZW F1 mice [6,7] and reduce the incidence of breast tumors in rats [8].
The 1980s were a period of expansion in our knowledge about PUFAs in general and omega-3 fatty acids in particular. Today we know that omega-3 fatty acids are essential for normal growth and development and may play an important role in the prevention and treatment of coronary artery disease, hypertension, arthritis, other inflammatory and autoimmune disorders and cancer [9]. Research has been carried out in animal models, tissue cultures and human beings. The original observational studies have given way to controlled clinical trials.
In this paper, I review the anti-inflammatory aspects of omega-3 fatty acids relative to prostaglandins and cytokines and their clinical effects in inflammatory and autoimmune diseases, such as cardiovascular disease, major depression, arthritis, inflammatory bowel disease, asthma and psoriasis.

	Omega-6 and Omega-3 Fatty Acids and Prostaglandin Metabolism

Omega-6 fatty acids account for the majority of polyunsaturated fatty acids (PUFA) in the food supply. They are the predominant PUFA in all diets, especially Western diets. When diets are supplemented with omega-3 fatty acids, the latter partially replace the omega-6 fatty acids in the membranes of practically all cells (i.e., erythrocytes, platelets, endothelial cells, monocytes, lymphocytes, granulocytes, neuronal cells, fibroblasts, retinal cells, hepatic cells and neuroblastoma cells).
Competition between the omega-6 and omega-3 fatty acids occurs in prostaglandin formation. Eicosapentaenoic acid (EPA), an omega-3 fatty acid, competes with arachidonic acid (AA), an omega-6 fatty acid, for prostaglandin and leukotriene synthesis at the cyclooxygenase and lipoxygenase level(Fig. 1). When humans ingest fish or fish oil, the EPA and docosahexaenoic acid (DHA) from fish or fish oil lead to (1) a decreased production of prostaglandin E2 (PGE2) metabolites, (2) a decrease in thromboxane A2, a potent platelet aggregator and vasoconstrictor (3) a decrease in leukotriene B4 formation, an inducer of inflammation and a powerful inducer of leukocyte chemotaxis and adherence, (4) an increase in thromboxane A3, a weak platelet aggregator and a weak vasoconstrictor, (5) an increase in prostacyclin PGI3, leading to an overall increase in total prostacyclin by increasing PGI3 without a decrease in PGI2 (both PGI2 and PGI3 are active vasodilators and inhibitors of platelet aggregation) and (6) an increase in leukotriene B5, a weak inducer of inflammation and a weak chemotactic agent [10,11]. Omega-3 fatty acids modulate prostaglandin metabolism and decrease triglycerides and, in high doses, lower cholesterol and have antithrombotic and anti-inflammatory properties. These studies were extensively reviewed and reported [12–17].

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Fig. 1. Oxidative metabolism of arachidonic acid and eicosapentaenoic acid by the cyclooxygenase and 5-lipoxygenase pathways. 5-HPETE denotes 5-hydroperoxyeicosatetranoic acid and 5-HPEPE denotes 5-hydroxyeicosapentaenoic acid.

Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid mediators are released and play a crucial role. Pro-inflammatory eicosanoids of AA metabolism are released from membrane phospholipids in the course of inflammatory activation. EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.
A variety of substances that inhibit the COX pathway have been investigated, including non-steroidal anti-inflammatory drugs (NSAIDs) used for the treatment of inflammation, pain and fever. Although NSAIDs inhibit COX and are efficacious anti-inflammatory agents, serious adverse effects limit their use. Two forms of COX have been identified, a constitutively expressed COX-1 and a cytokine inducible COX-2. It has been suggested that NSAID toxicity is due to inhibition of COX-1, whereas therapeutic properties are derived from COX-2 inhibition at the site of inflammation [18,19]. In addition, there is evidence that COX-2 inhibition can suppress the growth of colorectal cancer [20].
A new arena for omega-3 fatty acids has emerged as adjuvants to drug treatment leading to synergism (potentiating the effects of drugs) or to decreasing their toxicity (Table 1) [21–32].

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Table 1. Conditions in which Omega-3 Fatty Acids Have Been Shown to Have Synergistic Effects with Drugs

Similarly, increasing the intake of omega-3 fatty acids while decreasing the omega-6 fatty acids in the diet has led to improvements and a decrease of non-steroidal anti-inflammatory agents in patients with rheumatoid arthritis [33,34] and asthma [35].
Dietary fish oils, rich in omega-3 PUFA, are rapidly incorporated into the membrane phospholipids of circulating human (monocyte) cells, suggesting that they are likely to have an effect on several aspects of cell function. Moderate dietary supplementation with omega-3 PUFA significantly increases their level in monocytes within two weeks [36]. The levels of EPA reached a maximum accumulation after six weeks’ supplementation and DHA reached a peak at 18 weeks [37]. EPA returned rapidly to pretreatment levels in monocytes (although plasma levels remained significantly elevated from baseline after 24 weeks of washout) whereas DHA levels declined more slowly [37].

	Omega-3 Fatty Acids, Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF)

The interactions between immune and inflammatory cells are mediated in large part by proteins, termed interleukins (IL), that are able to promote cell growth, differentiation and functional activation. TNF- and IL-1 and IL-6 are the most important cytokines produced by monocytes and macrophages. Production of appropriate amounts of TNF, IL-1 and IL-6 is beneficial in response to infection, but in inappropriate amounts or overproduction can be dangerous and these cytokines, especially TNF, are implicated in causing some of the pathological responses that occur in inflammatory conditions. They induce fever and the synthesis of acute phase proteins by the liver, activate T and B lymphocytes and endothelial cells and are involved in many other aspects of the acute phase response.
In addition to their anti-inflammatory effects by suppressing LTB4, omega-3 supplementation to healthy volunteers suppresses the capacity of monocytes to synthesize interleukin-1 (IL-1) and tumor necrosis factor (TNF)(Table 2) [38]. Omega-3 fatty acids suppress IL-1 mRNA [40,41]. These observations led to studies in patients with inflammatory and autoimmune diseases. The suppression of cytokine synthesis could also be achieved by dietary alteration without fish oil supplementation [34]. The cytokine suppression is probably achieved at the level of transcription, since IL-1 mRNA was decreased. This effect may account for the beneficial effects of omega-3 fatty acids in models of chronic inflammatory disease. IL-1 and TNF influence a wide array of biological functions [42]. Many of the biological functions of IL-1 are shared by TNF [43]. IL-1 potentiates procoagulent activity, increases production of plasminogen activator inhibitor and endothelin and the formation of eicosanoids. Furthermore, it increases leukocyte adhesion by inducing the expression of adhesion molecules and it promotes endothelial protein permeability.

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Table 2. Effects of Omega-3 Fatty Acids on Factors Involved in the Pathophysiology of Inflammation

Pharmacologic agents known to reduce the synthesis of IL-1 and TNF are corticosteroids and cyclosporin. Since IL-1 and TNF are principal mediators of inflammation, reduced production of these cytokines contributes to the amelioration of inflammatory symptoms in patients taking omega-3 fatty acid supplements. Studies in normal volunteers indicate that omega-3 fatty acid supplementation reduced the ability of monocytes to produce IL-1ß upon stimulation with endotoxin. The effect was most pronounced 10 weeks after stopping the supplementation and suggests prolonged incorporation of omega-3 fatty acids into a pool of circulating monocytes [44]. The capacity of the monocytes from these donors to synthesize IL-1ß returned to the pre-supplement level 20 weeks after ending supplementation. Similar results were observed for IL-1 and TNF. These findings have led to trials with omega-3 fatty acids since the above effects (suppression of such magnitude) have been observed and can only be achieved pharmacologically by administration of glucocorticoids or cyclosporin A, which have well-known adverse side effects, particularly during long-term administration. In a one-year intervention trial with dietary fish oil, 66 patients, after renal transplantation and on cyclosporin, randomized, double-blind study, 6 gm of fish oil daily (3 gm of omega-3 fatty acids), had a beneficial effect on renal hemodynamics and on blood pressure. Furthermore, the fish-oil group had significantly fewer rejection episodes than the control group, and there was a trend to increased graft survival [45]. In patients with IgA nephropathy, treatment with fish oil for two years retards the rate at which renal function is lost [46]. The omega-3 fatty acids in fish oil affect eicosanoid metabolism and cytokine production, two important classes of inflammatory modulators, and therefore have the potential to alter renal hemodynamics and inflammation. IgA nephropathy is the most common glomerular disease in the world. Omega-3 fatty acids lower plasma triglycerides and improve red cell flexibility in patients with lupus nephritis [47,48].
Caughey et al. [49] demonstrated that a diet enriched with flaxseed oil can inhibit the ex vivo production of these cytokines by 30% in four weeks, whereas nine grams of fish oil for another four weeks inhibited IL-1ß by 80% and TNF by 74%. Flaxseed increased EPA but not DHA levels in monocytes. Thromboxane A2 is a facilitator of cytokine synthesis in human monocytes [49]. Results of animal and human studies support the hypothesis that omega-3 PUFA suppress cell mediated immune responses, in part at least by inhibiting antigen presenting-cell function, increase membrane fluidity and alter the expression of membrane proteins, possibly by influencing the vertical displacement of the proteins within the membrane. Most of the human studies have shown that omega-3 fatty acids inhibit proinflammatory cytokines TNF and IL-1. Several studies performed in mice show that omega-3 fatty acids have a stimulatory effect on TNF and IL-1 [50–54]. This species-specific effect may be due to differences in the cell population affected by the PUFAs between the various species [55].
Omega-3 fatty acids suppress platelet activating factor (PAF). PAF is a potent platelet aggregator and leukocyte activator, and it strongly promotes AA metabolism(Table 2). It has been proposed that PAF, a phospholipase A2 (PLA2) dependent phospholipid, plays a crucial role in the pathogenesis of rheumatoid arthritis, asthma, endotoxin shock and acute renal transplant rejection.

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Received May 21, 2002. Accepted August 15, 2002.

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