Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Prostaglandins Leukot Essent Fatty Acids. Author manuscript; available in PMC 2010 August 1.
Published in final edited form as:
PMCID: PMC2755221

Dietary docosahexaenoic and eicosapentaenoic acid: Emerging mediators of inflammation


The inflammatory response is designed to help fight and clear infection, remove harmful chemicals, and repair damaged tissue and organ systems. Although this process, in general, is protective, the failure to resolve the inflammation and return the target tissue to homeostasis can result in disease, including the promotion of cancer. A plethora of published literature supports the contention that dietary n-3 polyunsaturated fatty acids (PUFA), and eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) in particular, are important modulators of a host's inflammatory/immune responses. The following review describes a mechanistic model that may explain, in part, the pleiotropic anti-inflammatory and immunosuppressive properties of EPA and DHA. In this review, we focus on salient studies that address three overarching mechanisms of n-3 PUFA action: (i) modulation of nuclear receptor activation, i.e., nuclear factor-κB (NF-κB) suppression; (ii) suppression of arachidonic acid–cyclooxygenase-derived eicosanoids, primarily prostaglandin E2-dependent signaling; and (iii) alteration of the plasma membrane micro-organization (lipid rafts), particularly as it relates to the function of Toll-like receptors (TLRs), and T-lymphocyte signaling molecule recruitment to the immunological synapse (IS). We propose that lipid rafts may be targets for the development of n-3 PUFA-containing dietary bioactive agents to down-modulate inflammatory and immune responses and for the treatment of autoimmune and chronic inflammatory diseases.

1. Introduction

Complementary and alternative medicine is commonly practiced by Americans (40-60%) to ameliorate an array of diseases and to promote optimal health [1]. With respect to dietary lipids, the anti-inflammatory properties of fish oil, containing long-chain n-3 polyunsaturated fatty acids (PUFA), has been extensively evaluated in experimental rodent and cell culture model systems over the past three decades. A plethora of dietary studies using rodent species have demonstrated that dietary fish oil reduces pro-inflammatory responses, in part, by diminishing T-cell proliferative capacity in response to mitogenic stimuli and antigenic stimulation [2-6]. Similar suppressive effects were observed with respect to the dendritic cell, endothelial cell, macrophage, and neutrophil components of the inflammatory response [7-12]. By using purified diets enriched with fish oil or eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) ethyl esters, a number of studies have demonstrated that both EPA and DHA are bioactive and suppress antigen-specific delayed hypersensitivity reactions and mitogen-induced proliferation of T-cells, as well as modulate murine T-helper cell (Th1/Th2) balance [13-15]. The loss of lymphoproliferative activity was accompanied by reduction in interleukin (IL)-2 secretion and IL-2 receptor α chain mRNA transcription, suggesting that dietary n-3 PUFA act, in part, by interrupting the autocrine IL-2 activation pathway [16]. In addition, dietary DHA blunted the production of intracellular second messengers, including diacylglycerol and ceramide, following mitogen stimulation ex vivo [16-18]. These data conclusively demonstrate that dietary n-3 PUFA modulate components of the intracellular signaling pathways regulating T-cell activation. In theory, these alterations in T-cell function could reflect both the direct effects of dietary n-3 PUFA in impairing the ability of the target T-cell population to respond to activating stimuli, and the indirect effects of n-3 PUFA on the activity of other cells (accessory cells or other T-cell populations) to suppress the response of the target cells; or a combination of these two distinct mechanisms. Most previous studies addressing these issues have been carried out in unseparated populations of T-cells and accessory cells stimulated with mitogenic agents, which act indiscriminantly on generic T-cell surface ligands. Our laboratory demonstrated that n-3 PUFA affect T-cell receptor-mediated activation by both direct and indirect (accessory cell) mechanisms [19]. Other studies have affirmed these observations [11,20].

2. Immunosuppressive effects of n-3 PUFA in humans

Epidemiological data collected in the 1970s indicate that Greenland Eskimos, who typically consume large amounts of n-3 PUFA, have a decreased incidence of inflammatory disease relative to Americans. Similar observations were made in the Japanese population, which led to the correlation between a decreased incidence of inflammatory disease and increased cold water fish consumption [21,22]. Although scientists have tested the effects of dietary fish oil supplementation in humans, in general, the data are inconclusive regarding the ability of n-3 PUFA to suppress chronic inflammatory diseases. For example, there have been at least 14 randomized placebo-controlled double-blind studies of n-3 PUFA-rich fish oil in patients with rheumatoid arthritis (see review, [22]). Several investigators have reported that patients consuming n-3 PUFA supplements were able to lower or discontinue their anti-inflammatory drugs [23,24]. However, confirmatory, definitive studies are needed in order to make recommendations for clinical practice. Although a growing body of published reports support the contention that n-3 PUFA are safe and may be effective for maintenance of remission of inflammatory bowel diseases (IBD) [25-29], there are not sufficient data to recommend the routine use of EPA/DHA for maintenance of remission in IBD. Similarly, with regard to airway inflammation, which is a major component of asthma, preliminary research indicates that certain subjects with bronchial asthma may respond favorably to fish oil supplementation [30-33]. Therefore, while these clinical studies are promising, additional research clearly is required.

3. Human cytokines

Inflammation is a component of several acute and chronic human diseases, and is characterized by activation/production of at least four classes of active compounds: (i) inflammatory cytokines, (ii) arachidonic acid (AA) (20:4n-6)-derived eicosanoids, (iii) inflammatory mediators (e.g., platelet activating factor), and (iv) adhesion molecules. In order to evaluate the therapeutic value of long-chain n-3 PUFA, a number of investigators have examined the effect of diet on blood inflammatory cell populations and plasma biomarkers of inflammation in healthy adults. In general, the consumption of EPA and DHA are associated with lower levels of inflammatory mediators and soluble adhesion molecules [7,30,3438]. In contrast, alpha linolenic acid (18:3n-3), a precursor to EPA and DHA, may not elicit anti-inflammatory effects [39,40].

It is now apparent that chronic inflammatory diseases are characterized by interactions among multiple genes and environmental factors such as diet [41]. Hence, it is important to understand the role of genetic variation in inflammation and chronic disease. More specifically, it is likely that the complex effects of n-3 PUFA on cytokine biology and plasma biomarkers of inflammation can be explained, in part, by polymorphisms and genotypes of the responsive subjects [42,43]. With regard to dietary lipid source, both the relative and absolute dietary intake of n-3 and n-6 PUFA, which compete for the same transport and acylation pathways, influence the tissue levels of EPA and DHA [44]. This is further complicated by the fact that common genetic variants of the FADS1/FADS2 gene cluster differently convert n-3 and n-6 PUFA catalyzed by the Δ5 and Δ6 desaturase, respectively [45]. Other factors that may influence the effects of long-chain n-3 PUFA on immune function in healthy humans include dose-related effects [46] and age [46,47]. Indeed, there is some evidence that dietary EPA and DHA may differentially influence immune cell function in healthy human subjects [48]. For example, DHA, but not EPA, suppressed T-cell activation as assessed by CD69 expression [49]. Clearly, additional work is needed in order to elucidate the distinct anti-inflammatory properties of EPA and DHA. The following sections describe three mechanistic models that accommodate diverse views on the immunosuppressive properties of n-3 PUFA.

4. Putative mechanisms of action

Lipid rafts and long-chain n-3 PUFA

There are a number of mechanisms which functionally link the pleiotropic effects of EPA and DHA to inflammation. Examples include (i) alteration of membrane self-organizing lipid raft domains, (ii) modulation of nuclear receptor activation, and (iii) metabolic interconversion into bioactive eicosanoids/docosanoids (Fig. 1).

Fig. 1
Proposed molecular model by which EPA and DHA modulate immune cell function and inflammation. n-3 PUFA suppress nuclear receptor activation, e.g., NF-κB, arachidonic acid-cyclooxygenase-derived eicosanoids, and alter plasma membrane micro-organization ...

Defining the molecular and cellular mechanisms that regulate immunological homeostasis is the focus of intense research. Recent studies on the various functional capacities of T-cells and antigen-presenting cells, e.g., dendritic cells, have demonstrated the presence of specific detergent-resistant domains (rafts) in which key signal-transduction proteins are localized. Typically, upon cell activation, rafts compartmentalize the activated receptor complexes and associated signal-transducing molecules, thus providing an environment conducive to signal transduction [50]. While evidence for the existence of lipid rafts in the plasma membrane has provoked debate, new sophisticated imaging approaches have started to define cell surface nanoscale organization [51-53]. Recently, a number of investigators have documented the unique membrane altering properties of long-chain n-3 PUFA (see [54,55] for details). Data from these and other studies demonstrate that DHA is a unique fatty acid, because it significantly alters basic properties of cell membranes, including fatty acid chain order and fluidity, phase behavior, elastic compressibility, ion permeability, fusion, rapid flip-flop, and resident protein function [55,56]. Because of its polyunsaturation, DHA is sterically incompatible with sphingolipid and cholesterol and, therefore, is capable of altering lipid raft behavior and protein function in living cells [14,57,58]. Although the complexity of this issue precludes drawing any conclusions, based on our observations [14,57-60], we have hypothesized that dietary DHA alters plasma membrane microdomain lipid composition, thereby directly influencing protein signaling complexes that regulate immune responses and inflammation. Alternatively, DHA may inhibit signaling protein post-translational lipidation, which subsequently may alter lipid raft targeting and protein function. This may explain how DHA elicits immunological hyporesponsiveness, thereby suppressing inflammatory mediators in humans. Unfortunately, no studies to date have compared the membrane altering domain properties of DHA with EPA in innate immune cells with antigen-presenting function or conventional T-cell populations.

The mechanisms by which the body senses the diverse molecular factors that trigger inflammation have recently been elucidated. The recognition of conserved pathogen-associated molecular patterns (PAMPs) enables the innate immune system to generate an appropriate immune response [61]. Germline encoded pattern recognition receptors (PRRs) include Toll-like receptors (TLRs), Nod-like receptors (NLRs), and C-type lectin receptors, all of which regulate immune activation in response to diverse stimuli, including infection and tissue injury. It is now recognized that the lipid components of the diet can modulate transmembrane TLRs and the consequent inflammatory and immune responses. In a series of seminal findings, Hwang and colleagues demonstrated that DHA acts as a pan-inhibitor of various TLRs and NLRs, suppressing nuclear factor-κB (NF-κB)-related signal transduction [20,62,63]. These data provide a putative link between n-3 PUFA, NF-κB, innate immunity (epithelial cells, macrophages, dendritic cells), and adaptive immune (T-cells) responses. Interestingly, lipid rafts have been implicated in the regulation and activation of TLR signaling complexes [64,65]. It is currently unclear whether alteration of lipid rafts by n-3 PUFA is a major mechanism by which DHA alters TLR signaling in a variety of cell types.

Effects of n-3 PUFA on eicosanoid/docosanoid metabolism

The long-chain n-3 PUFA present in dietary fish oil, EPA and DHA, affect diverse physiological processes by dampening arachidonic acid-derived eicosanoid (prostaglandin and leukotriene) signaling [10,66]. This is significant because AA-derived mediators can act to both promote and inhibit inflammation [67-69]. Interestingly, the AA pool(s) for eicosanoids in humans is not quickly influenced by dietary n-6 PUFA because of a large pool(s) size of AA and a low conversion of metabolic precursors to AA. In contrast, the n-3 PUFA pool(s), which is considerably smaller, is immediately influenced by n-3 PUFA supplementation [70]. Recently described resolvins, docosatrienes, and neuroprotectins derived from EPA and DHA represent endogenous biochemical mediators that can counter-regulate inflammation [71]. Given their potent bioactivity, it is now clear that these n-3 PUFA metabolites contribute to the termination of inflammation [72]. With respect to disease states, lipid mediator informatics-lipidomics approaches suggest that the biosynthesis of these proresolving molecules may be defective in patients with chronic inflammation [69,71].

Although EPA is normally found in much lower abundance than DHA in tissues [66], the recent discovery of EPA-derived novel autoxidation has generated much interest in the inflammation field [73]. Non-enzymatic highly reactive cyclopentenone isoprostane compounds (A3/J3-isoprostanes) appear capable of activating NF-E2-related factor 2 which, in turn, can enhance antioxidant gene expression that regulates detoxification of reactive oxygen species [74]. At present, further work is needed to understand precisely how n-6/n-3 PUFA consumption modulates non-enzymatic and enzymatically oxidized proresolving forms of EPA and DHA.

Nuclear receptor activation/gene transcription

Additional insight into the mechanisms by which dietary n-3 PUFA inhibit inflammatory responses was provided by the identification of several nuclear receptors, e.g., peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors, which are activated at micromolar concentrations by EPA and DHA [75-78]. Interestingly, PPARs can transrepress inflammatory responses mediated by the transcription factor NF-κB [79]. This is significant because activation of NF-κB appears to link inflammation and immunity to cancer development and progression [80,81]. Other molecular pathways that do not require PPARs and may be involved in the PUFA-mediated regulation of inflammation include hepatocyte nuclear factor 4α (HNF4α) [82]. Interestingly, EPA and DHA-CoA thioesters may act as suppressor ligands of HNF4α [83].

In summary, a growing number of dietary supplementation studies using healthy human subjects, as well as animal disease models, have clearly shown dietary fish oil to possess anti-inflammatory properties. The primary effector molecules are n-3 fatty acids, EPA, and DHA, which are present in relatively low quantities in the western diet. Although the mechanisms of EPA and DHA action are still not fully defined in molecular terms, it is becoming increasingly clear that these long-chain fatty acids alter immune cell membrane lipid microdomain properties, modulate nuclear receptor activation, and alter the spectrum of cyclooxygenase and lipoxygenase metabolites, which collectively may explain their pleiotropic properties (Fig. 1). Unfortunately, at present there are limited data to support the notion that n-3 PUFA ameliorate clinical symptoms in patients affected by diseases characterized by active inflammation. It is highly likely that genetic differences contribute to variable response to n-3 PUFA supplementation, making it difficult to determine how best to use EPA and/or DHA in the prevention and/or treatment of inflammatory and autoimmune diseases.

In conclusion, this workshop on DHA as a required nutrient raised some important issues. If DHA has significant health benefits for humans, which can be documented, then a DRI value should be considered. For the nutrient to be “required” means that it is unlikely to be obtained in sufficient amounts from a precursor substance and thus a specified amount would have to be obtained as DHA per se. Data summarized by Burdge and Calder [84] suggest that the conversion of alpha linolenic acid to DHA is less than 0.5% and that the beneficial effects of DHA occur at the level of 500 mg/day. This gap between intake and efficacy suggests that DHA is conditionally essential and that a DRI value for DHA should be considered. The next consideration is the selection of an endpoint for the determination of a DRI value. From the reports presented, it is unlikely that anti-inflammation would be the most important endpoint, since this is an emerging field rather than having coronary heart disease (CHD) as the endpoint for which there are extensive data. However, the anti-inflammatory data presented in this paper are important because they provide a clear biological mechanism(s) by which DHA may exert its beneficial effect. Since inflammation is considered to have a major impact on CHD, if CHD risk reduction is used as the endpoint for a DRI value for DHA, then these data on inflammation could be used to help establish a mechanistic basis.


Designing Foods for Health is gratefully acknowledged. RSC, WK, JL, and DNM have no conflicts of financial or personal interest in any company or organization sponsoring the research, including advisory board affiliations. RSC, WK, JL, and DNM compiled data from collaborative experiments and evaluated the literature.


Sources of support: National Institutes of Health Grants CA59034, CA129444, DK071707, and P30ES09106; US Department of Agriculture Grant 2006-34402-17121, “Designing Foods for Health”.


1. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 fatty acid supplementation for inflammatory joint pain. Pain. 2007;129:210–223. [PubMed]
2. Arrington JJ, McMurray DN, Switzer KC, Fan YY, Chapkin RS. Docosahexaenoic acid suppresses function of the CD28 costimulatory membrane receptor in primary murine and Jurkat T cells. J Nutr. 2001;131:1147–1153. [PubMed]
3. Arrington JL, Chapkin RS, Switzer KC, Morris JS, McMurray DN. Dietary n-3 polyunsaturated fatty acids modulate purified murine T-cell subset activation. Clin Exp Immunol. 2001;123:1–10. [PubMed]
4. Anderson MJ, Fritsche KL. Dietary polyunsaturated fatty acids modulate in vivo, antigen-driven CD4+ T-cell proliferation in mice. J Nutr. 2004;134:1978–1983. [PubMed]
5. Zhang P, Smith R, Chapkin RS, McMurray DN. Dietary (n-3) polyunsaturated fatty acids modulate murine Th1/Th2 balance toward the Th2 pole by suppression of Th1 development. J Nutr. 2005;135:1745–1751. [PubMed]
6. Zhang P, Kim W, Zhou L, et al. Dietary fish oil inhibits murine antigen-specific Th1 cell development by suppression of clonal expansion. J Nutr. 2006;136:2391–2398. [PubMed]
7. Prescott SM. The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils. J Biol Chem. 1984;259:7615–7621. [PubMed]
8. Hughes DA, Pinder AC. n-3 polyunsaturated fatty acids inhibit the antigen-presenting function of human moncytes. Am J Clin Nutr. 2000;71(Suppl):357S–360S. [PubMed]
9. Novak TE, Babcock TA, Jho DH, Helton WS, Espat NJ. NF-κB inhibition by ω-3 fatty acids modulates LPS-stimulated macrophage TNFalpha transcription. Am J Physiol Lung Cell Mol Physiol. 2003;284:L84–L89. [PubMed]
10. Bagga D, Wang L, Farias-Eisner R, Glaspy JA, Reddy ST. Differential effects of prostaglandin derived from ω-6 and ω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci. 2003;100:1751–1756. [PubMed]
11. Zeyda M, Saemann MD, Stuhlmeir KM, et al. Polyunsaturated fatty acids block dendritic cell activation and function independently of NF-κB activation. J Biol Chem. 2005;280:14293–14301. [PubMed]
12. Massaro M, Scoditti E, Carluccio MA, Montinari MR, De Caterina R. Omega-3 fatty acids, inflammation and antiogenesis: nutrigenomic effects as an explanation for anti-atherogenic and anti-inflammatory effects of fish and fish oils. J Nutrigenet Nutrigenomics. 2008;1:4–23. [PubMed]
13. Fowler KH, Chapkin RS, McMurray DN. Effects of purified n-3 ethyl esters on murine T lymphocyte function. J Immunol. 1993;151:5186–5197. [PubMed]
14. Fan YY, Ly LH, Barhoumi R, McMurray DN, Chapkin RS. Dietary docosahexaenoic acid suppresses T-cell protein kinase C-theta lipid raft recruitment and interleukin-2 production. J Immunol. 2004;173:6151–6160. [PubMed]
15. Ly LH, Smith R, Switzer KC, Chapkin RS, McMurray DN. Dietary eicosapentaenoic acid modulates CTLA-4 expression in murine CD4+ T-cells. Prost Leuk Essent Fatty Acids. 2006;74:29–37. [PubMed]
16. Jolly CA, Jiang YH, Chapkin RS, McMurray DN. Dietary n-3 polyunsaturated fatty acid modulation of murine lymphoproliferation and interleukin-2 secretion: correlation with alterations in diacylglycerol and ceramide mass. J Nutr. 1997;127:37–43. [PubMed]
17. Fowler KH, McMurray DN, Fan YY, Aukema HM, Chapkin RS. Purified dietary n-3 polyunsaturated fatty acids alter diacylglycerol mass and molecular species composition in concavalin A-stimulated murine splenocytes. Biochim Biophys Acta. 1993;1210:89–96. [PubMed]
18. Jolly CA, Laurenz JC, McMurray DN, Chapkin RS. Diacylgycerol and ceramide kinetics in primary cultures of activated T-lymphocytes. Immunol Lett. 1996;49:43–48. [PubMed]
19. Chapkin RS, Arrington JL, Apanasovich TV, Carroll RJ, McMurray DN. Dietary n-3 PUFA affect TCR-mediated activation of purified murine T cells and accessory cell function in co-cultures. Clin Exp Immunol. 2002;130:12–18. [PubMed]
20. Weatherill AR, Lee JY, Zhao L, Lemay DG, Youn HS, Hwang DH. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated by TLR4. J Immunol. 2005;174:5390–5397. [PubMed]
21. Calder PC. n-3 polyunsaturated fatty acids, inflammation and immunity: pouring oil on troubled water or another fishy tale? Nutr Res. 2001;21:309–341.
22. Calder PC. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83(Suppl):1505S–1519S. [PubMed]
23. Kremer JM, Jubiz W, Michalek A, et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis. Ann Intern Med. 1987;106:497–502. [PubMed]
24. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr. 2000;71(Suppl):349S–351S. [PubMed]
25. Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med. 1996;334:1557–1560. [PubMed]
26. Belluzzi A, Boschi S, Brignola C, Munarini A, Cariani G, Miglio M. Polyunsaturated fatty acids and inflammatory bowel disease. Am J Clin Nutr. 2000;71(Suppl):339S–342S. [PubMed]
27. Turner D, Zlotkin SH, Shah PS, Griffiths AM. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2007;2 [PubMed]
28. Turner D, Steinhart AH, Griffiths AM. Omega 3 fatty acids (fish oil) for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;3 [PubMed]
29. De Ley M, de Vos R, Hommes DW, Stokkers P. Fish oil induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;4 [PubMed]
30. Von Schacky C, Kiefl R, Jendraschak E, Kaminski WE. n-3 fatty acids and cysteinyl-leukotrience formation in humans in vitro, ex vivo and in vivo. J Lab Clin Med. 1993;121:302–309. [PubMed]
31. Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K. Dietary supplementation with fish oil rich in ω-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J. 2000;16:861–865. [PubMed]
32. Stephensen CB. Fish oil inflammatory disease: is asthma the next target for n-3 fatty acid supplements? Nutr Rev. 2004;62:486–489. [PubMed]
33. Schachter HM, Reisman J, Tran K, et al. Health effects of omega-3 fatty acids on asthma. Summary, Evidence Report/Technology Assessment No. 91, AHRQ Publication No. 04-E013–1. Agency for Healthcare Research and Quality; Rockville, MD: 2004. Mar, [PubMed]
34. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med. 1989;320:265–271. [PubMed]
35. Kelly DS, Taylor PC, Nelson GJ, et al. Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men. Lipids. 1999;34:317–324. [PubMed]
36. Thies F, Miles EA, Nebe-von-Caron G, et al. Influence of dietary supplementation with long-chain n-3 and n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults. Lipids. 2001;36:1183–1193. [PubMed]
37. Lopez-Garcia E, Schulze MB, Manson JE, et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial in women. J Nutr. 2004:1806–1811. [PubMed]
38. Luu NT, Madden J, Calder PC, et al. Dietary supplementation with fish oil modifies the ability of human monocytes to induce an inflammatory response. J Nutr. 2007;137:2769–2774. [PubMed]
39. Kew S, Banerjee T, Minihane AM, et al. Lack of effect of foods enriched with plant- or marine-derived n-3 fatty acids on human immune function. Am J Clin Nutr. 2003;77:1287–1295. [PubMed]
40. Zhao G, Etherton TD, Martin KR, Gillies PJ, West SG, Kris-Etherton PM. Dietary α-linolenic acid inhibits proinflammatory cytokine production by peripheral blood mononuclear cells in hypercholesterolemic subjects. Am J Clin Nutr. 2007;85:385–391. [PubMed]
41. Kornman KS. Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging. Am J Clin Nutr. 2006;83(Suppl):475S–483S. [PubMed]
42. Grimble RF, Howell WM, O'Reilly G, et al. The ability of fish oil to suppress tumor necrosis factor α production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor α production. Am J Clin Nutr. 2002;76:454–459. [PubMed]
43. Shen J, Arnett DK, Peacock JM, et al. Interleukin1β genetic polymorphisms interact with polyunsaturated fatty acids to modulate risk of the metabolic syndrome. J Nutr. 2007;137:1846–1851. [PubMed]
44. Chapkin RS, McMurray DN, Lupton JR. Colon cancer, fatty acids and anti-inflammatory compounds. Curr Opin Gastroenterol. 2007;23:48–54. [PubMed]
45. Schaeffer L, Gohike H, Muller M, et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet. 2006;15:1745–1756. [PubMed]
46. Rees D, Miles EA, Banerjee T, et al. Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr. 2006;83:331–342. [PubMed]
47. Meydani SN, Endres S, Woods MM, et al. Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J Nutr. 1991;121:547–555. [PubMed]
48. Sierra S, Lara-Villoslalda F, Comalada M, Olivares M, Xaus J. Dietary eicosapentaenoic acid and docosahexaenoic acid equally incorporate as docosahexaenoic acid but differ in inflammatory effects. Nutrition. 2008;24:245–254. [PubMed]
49. Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, Yaqoob P. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am J Clin Nutr. 2004;79:674–681. [PubMed]
50. Jury EC, Flores-Borja F, Kabouridis PS. Lipid rafts in T cell signalling and disease. Semin Cell Dev Biol. 2007;18:608–615. [PMC free article] [PubMed]
51. Gaus K, Chklovskaia E, Fazekas de St Groth B, Jessup W, Harder T. Condensation of the plasma membrane at the site of T lymphocyte activation. J Cell Biol. 2005;171:121–131. [PMC free article] [PubMed]
52. Hancock JF. Lipid rafts: contentious only from simplistic standpoints. Nat Rev Mol Cell Biol. 2006;7:456–462. [PMC free article] [PubMed]
53. Jacobson K, Mouritsen OG, Anderson RGW. Lipid rafts: at a crossroad between cell biology and physics. Nat Cell Biol. 2007;9:7–14. [PubMed]
54. Zimmerberg J, Gawrisch K. The physical chemistry of biological membranes. Nat Chem Biol. 2006;2:564–567. [PubMed]
55. Wassall SR, Stillwell W. Docosahexaenoic acid domains: the ultimate non-raft membrane domain. Chem Phys Lipids. 2008;153:57–63. [PubMed]
56. Stillwell W, Wassall SR. Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids. 2003;126:1–27. [PubMed]
57. Fan YY, McMurray DN, Ly LH, Chapkin RS. Dietary (n-3) polyunsaturated fatty acids remodel mouse T-cell lipid rafts. J Nutr. 2003;133:1913–1920. [PubMed]
58. Chapkin RS, Wang N, Fan YY, Lupton JR, Prior IA. Docosahexaenoic acid alters the size and distribution of cell surface microdomains. Biochim Biophys Acta. 2008;1778:466–471. [PMC free article] [PubMed]
59. Ma DWL, Seo J, Davidson LA, et al. n-3 PUFA alter caveolae lipid composition and resident protein localization in mouse colon. Faseb J. 2004;18:1040–1042. [PubMed]
60. Ma DWL, Seo J, Switzer KC, et al. n-3 PUFA and membrane microdomains: a new frontier in bioactive lipid research. J Nutr Biochem. 2004;15:700–706. [PubMed]
61. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. [PubMed]
62. Lee JY, Plakidas A, Lee WH, et al. Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res. 2003;44:479–486. [PubMed]
63. Zhao L, Kwon MJ, Huang S, et al. Differential modulation of nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells. J Biol Chem. 2007;282:11618–11628. [PubMed]
64. Lee HK, Dunzendorfer S, Soldau K, Tobias PS. Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity. 2006;23:301–304. [PubMed]
65. Nakahira K, Kim HP, Geng XH, et al. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts. J Exp Med. 2006;203:2377–2389. [PMC free article] [PubMed]
66. Smith WL. Cyclooxygenases, peroxide tone and the allure of fish oil. Curr Opin Cell Biol. 2005;17:174–182. [PubMed]
67. Tilley SL, Coffman TM, Koller BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001;108:15–23. [PMC free article] [PubMed]
68. Mandal AK, Zhang Z, Kim SJ, Tsai PC, Mukherjee AB. Cutting edge: yin-yang: balancing act of prostaglandins with opposing functions to regulate inflammation. J Immunol. 2005;175:6271–6273. [PubMed]
69. Mangino MJ, Brounts L, Harms B, Heise C. Lipoxin biosynthesis in inflammatory bowel disease. Prost Lipid Mediators. 2006;79:84–92. [PubMed]
70. Hamazaki T, Fischer S, Urakaze M, Sawazaki S, Yano S, Kuwamori T. Urinary excretion of PGI2/3-M and recent n-6/3 fatty acid intake. Prostaglandins. 1989;37:417–424. [PubMed]
71. Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid mediators. Annu Rev Pathol Mech Dis. 2008;3:279–312. [PMC free article] [PubMed]
72. Flower RJ, Perretti M. Controlling inflammation: a fat chance? J Exp Med. 2005;201:671–674. [PMC free article] [PubMed]
73. Yin H, Brooks JD, Gao L, Porter NA, Morrow JD. Identification of novel autoxidation products of the ω-3 fatty acid eicosapentaenoic acid in vitro and in vivo. J Biol Chem. 2007;282:29890–29901. [PubMed]
74. Brooks JD, Milne GL, Yin H, Sanchez SC, Porter NA, Morrow JD. Formation of highly reactive cyclopentenone isoprostane compounds (A3/J3-isoprostanes) in vivo from eicosapentaenoic acid. J Biol Chem. 2008;283:12043–12055. [PMC free article] [PubMed]
75. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ Proc Natl Acad Sci USA. 1997;94:4318–4323. [PubMed]
76. Xu HE, Lambert MH, Montana VG, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 1999;3:397–403. [PubMed]
77. De Urquiza AM, Liu S, Sjoberg M, et al. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science. 2000;290:2140–2144. [PubMed]
78. Fan YY, Spencer TE, Wang N, Moyer MP, Chapkin RS. Chemoprotective n-3 fatty acids activate RXRα in colonocytes. Carcinogenesis. 2003;24:1541–1548. [PMC free article] [PubMed]
79. Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response by PPARγ Nature. 2005;437:759–763. [PMC free article] [PubMed]
80. Karin M, Greten FR. NF-κB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;10:749–759. [PubMed]
81. Karrasch T, Jobin C. NF-κB and the intestine: friend or foe? Inflamm Bowel Dis. 2008;14:114–124. [PubMed]
82. Ahn SH, Shah YM, Inoue J, et al. Hepatocyte nuclear factor 4α in intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis. 2008 March 13; [PMC free article] [PubMed]
83. Hertz R, Magenheim J, Berman I, Bar-Tana J. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature. 1998;392:512–516. [PubMed]
84. Burdge GC, Calder PC. Dietary alpha-linolenic acid and health-related outcomes: a metabolic perspective. Nutr Res Rev. 2006:26–52. [PubMed]