Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells

Dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) has been found to affect inflammation and metabolism, and many researchers have shown that omega-3 PUFAs provide benefits in immunologic and metabolic disorders. These effects were assumed to result mainly from a modification in the production of inflammatory mediators and the suppression of inflammatory leukocytes. Among PUFAs, eicosapentaenoic acid (EPA), a component of fish oil, apparently has the most potent effect. Recently, much research has focused on regulatory T cells (Tregs) as controllers of immune responses not only to self-antigens but also to non-self-antigens, including donor alloantigens. Therefore, induction of antigen-specific Tregs may be an attractive strategy for managing autoimmune diseases and transplant rejection. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear receptor that regulates lipid and glucose metabolism, can be activated by thiazolidinediones, fatty acids, and eicosanoids, including EPA. PPARγ was recently found to have immunoregulatory effects, and a PPARγ agonist inhibited immune responses in a rat model of autoimmune disease. Furthermore, in a murine model, one high dose of purified EPA given the day of transplantation induced marked prolongation of cardiac allograft survival in a dose-dependent manner. These findings suggest that EPA induced Tregs by means of a PPARγ-dependent mechanism. This review describes the immunomodulatory effects of PUFAs, especially EPA, and summarizes recent research that may have implications for the development of therapies for autoimmune diseases and transplant rejection that are based on induction of Tregs.