Omega-3

Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases-2

The Center for Genetics, Nutrition and Health, Washington, D.C

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 producedby 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, especiall TNF, are implicated in causing some of the pathological responses that occur in inflammatory conditions. They induce fever and the synthesis of acutephase 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.
 
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-1
B 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-1
B 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-1
B 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.