AJCN 19th International Congress of Nutrition
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by James, M. J
Right arrow Articles by Cleland, L. G
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by James, M. J
Right arrow Articles by Cleland, L. G
Agricola
Right arrow Articles by James, M. J
Right arrow Articles by Cleland, L. G
American Journal of Clinical Nutrition, Vol. 71, No. 1, 343S-348s, January 2000
© 2000 American Society for Clinical Nutrition

Supplements

Dietary polyunsaturated fatty acids and inflammatory mediator production1,2

Michael J James, Robert A Gibson and Leslie G Cleland

1 From the Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia, and the Department of Pediatrics and Child Health, Flinders Medical Center, Bedford Park, Australia.

2 Reprints not available. Address correspondence to MJ James, Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia 5000.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
 REFERENCES
 
Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid {alpha}-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE2 and LTB4, and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB4. Regarding the proinflammatory ctyokines, tumor necrosis factor {alpha} and interleukin 1ß, studies of healthy volunteers and rheumatoid arthritis patients have shown <=90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.

Key Words: Inflammation • fish oil • flaxseed • eicosapentaenoic acid • cytokine • prostaglandin • eicosanoid • n-3 fatty acid • polyunsaturated fatty acid


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
 REFERENCES
 
Inflammation is characterized symptomatically by pain, redness, and swelling; disordered or excessive inflammation also entails loss of function. This clinical pathology results from the release of inflammatory mediators, predominantly from activated leukocytes that migrate into the target area. Among the key inflammatory mediators are the n-6 eicosanoids, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), which are derived from the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA; 20:4n-6) (1). Also important are the cytokines, interleukin 1ß (IL-1ß) and tumor necrosis factor {alpha} (TNF-{alpha}), and there is strong evidence for the involvement of TNF-{alpha} in the joint pathology of rheumatoid arthritis (2, 3).

Many antiinflammatory pharmacotherapies are directed at inhibiting the production of these inflammatory mediators and thus possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. However, there are competitive interactions between dietary PUFAs; thus, in any examination of the effects of dietary n-3 or n-9 PUFAs, it is important to consider also the background dietary n-6 PUFAs.


   POLYUNSATURATED FATTY ACIDS IN THE DIET
TOP
 ABSTRACT
 INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
 REFERENCES
 
In the typical Western diet, 20–25-fold more n-6 fats than n-3 fats are consumed (4). This predominance of n-6 fat is due to the abundance in the diet of linoleic acid (LA; 18:2n-6), which is present in high concentrations in soy, corn, safflower, and sunflower oils. By contrast, there is a low intake of the n-3 homologue of LA, {alpha}-linolenic acid (ALA; 18:3n-3), which is present in leafy green vegetables and in flaxseed and canola oils. Once ingested, the 18-carbon fatty acids are desaturated and elongated to 20-carbon n-6 fatty acids. LA is converted to AA and ALA is converted to eicosapentaenoic acid (EPA; 20:5n-3). Compared with LA, there is little dietary intake of AA and EPA, which are present in meat and fish, respectively.

LA and ALA are necessary for complete health and cannot be synthesized in vertebrates; therefore, they are essential fatty acids. As a consequence, the relative dietary amounts of n-6 and n-3 fatty acids are determinants of the relative cellular amounts of LA and ALA (Figure 1Go).



View larger version (27K):
[in this window]
[in a new window]
  		FIGURE 1. . Dietary fatty acids and their metabolism after ingestion. Sunola oil; Meadow Lea Foods Ltd, Sydney, Australia.

 
Unlike the 18-carbon n-3 fatty acid ALA, oleic acid (18:1n-9), is consumed in substantial amounts in the typical Western diet and is not an essential fatty acid. There is little eicosatrienoic acid (ETA; 20:3n-9) in cell membranes, however, probably because of the overwhelming competition from dietary LA for the relevant desaturase and elongase enzymes (5) (Figure 1Go).


   EFFECT OF DIETARY n-3 AND n-9 FATS ON LIPID (EICOSANOID) INFLAMMATORY MEDIATORS
TOP
 ABSTRACT
 INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
 REFERENCES
 
PGE2 and LTB4 have proinflammatory biological actions. PGE2 can cause pain and vasodilation and LTB4 is a chemoattractant and activator of neutrophils; together they can cause vascular leakage and extravasation of fluid (1). Thus, the lipid mediators may be involved in the pain, redness, and swelling that occurs in acute inflammation.

AA is the progenitor of both PGE2 and LTB4 via the cyclooxygenase and 5-lipoxygenase enzymatic pathways, respectively. EPA, the n-3 homologue of AA, can inhibit AA metabolism competitively via these enzymatic pathways and, thus, can suppress production of the n-6 eicosanoid inflammatory mediators. EPA is a potential cyclooxygenase substrate for the synthesis of PGE3, which also has inflammatory activity, although PGE3 synthesis occurs with low efficiency or not at all (6, 7). EPA is also a 5-lipoxygenase substrate and can lead to the formation of LTB5, but LTB5 has little inflammatory activity compared with LTB4 (8, 9). Thus, increasing dietary n-3 fats can shift the balance of the eicosanoids produced to a less inflammatory mixture (Figure 2Go).



View larger version (7K):
[in this window]
[in a new window]
  		FIGURE 2. . Effect of n-3 and n-9 fatty acids on the production of lipid and peptide inflammatory mediators. The solid arrows indicate synthesis and the dashed arrows indicate inhibition. ETA, eicosatrienoic acid, LT, leukotriene; AA, arachidonic acid; PG, prostaglandin; TX, thromboxane; EPA, eicosapentaenoic acid; TNF-{alpha}, tumor necrosis factor {alpha}; IL-1ß, interleukin 1ß.

 
There is potential also for use of dietary ETA for antagonism of AA conversion to LTB4. ETA is a substrate of 5-lipoxygenase and although LTA3 formation occurs, LTA3 is a poor substrate but a good inhibitor of leukotriene-A4 hydrolase, the enzyme necessary for LTB4 synthesis in addition to arachidonate 5-lipoxygenase (10, 11). Inhibition of LTB4 synthesis via inhibition of leukotriene-A4 hydrolase has been observed in rats (12) and humans (13) during severe LA restriction, leading to elevated ETA concentrations. Furthermore, when ETA was included in the diet of (LA-sufficient) rats, it was incorporated into cell membranes and inhibited LTB4 synthesis via inhibition of leukotriene-A4 hydrolase (14–16). Thus, in partial analogy to the situation with EPA, increasing dietary ETA intake can also alter the balance of eicosanoids produced by leukocytes toward a potentially less inflammatory mixture (Figure 2Go). The effect of ETA on prostaglandin-endoperoxide synthase (cyclooxygenase) is less clear than that with 5-lipoxygenase. ETA lacks the n-6 double bond necessary for prostanoid formation, but may inhibit PGE2 production because inhibition of endothelial PGI2 production has been attributed to ETA (17).


   EFFECT OF DIETARY n-3 FATS ON PEPTIDE (CYTOKINE) INFLAMMATORY MEDIATORS
TOP
 ABSTRACT
 INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
 REFERENCES
 
The cytokines IL-1ß and TNF-{alpha} have proinflammatory cellular actions that include stimulating the production of collagenases (2, 18) and increasing the expression of adhesion molecules necessary for leukocyte extravasation (19). More direct biological evidence for the importance of these cytokines in inflammatory joint disease includes the observations that intraarticular IL-1ß causes arthritis in rabbits (20), that mice transgenic for a modified human TNF gene that is constitutively expressed develop polyarthritis that is prevented by anti-TNF monoclonal antibody (21), and that intravenous administration of anti-TNF-{alpha} monoclonal antibody to patients with rheumatoid arthritis suppresses joint inflammation (3). Whereas the eicosanoids may mediate much of the early pathology of inflammatory joint disease, such as swelling, pain, and leukocyte infiltration, cytokines have been implicated in the late, destructive phase of the disease, which includes cartilage loss, bone resorption, and, ultimately, joint failure (2).

Inclusion of n-3 fats in the diet can suppress the production of both TNF-{alpha} and IL-1ß. Fish oil is rich in the 20-carbon and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid (DHA; 22:6n-3) and it has been shown that dietary supplementation with encapsulated fish oil results in decreased monocyte synthesis of TNF-{alpha}, IL-1ß, or both in healthy subjects (22–24) and in patients with rheumatoid arthritis (25). Results of these studies are summarized in Table 1Go. Although it is known that fish-oil ingestion effectively elevates cellular concentrations of EPA and DHA, it is not known whether EPA, DHA, or both are involved in the suppression of cytokine production.


View this table:
[in this window]
[in a new window]
  		TABLE 1.. Studies reporting inhibition of tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin 1ß (IL-1ß) production after dietary fish oil supplementation1
 
An alternate approach to elevating cellular EPA concentrations is to increase intake of ALA, the progenitor of EPA. When flaxseed oil, which contains {approx}56% ALA, was used by healthy male volunteers in their domestic food preparation, leukocyte EPA concentrations were increased and both IL-1ß and TNF-{alpha} production were suppressed by {approx}30% after 4 wk (Figure 3Go) (24).



View larger version (19K):
[in this window]
[in a new window]
  		FIGURE 3. . Effect on cytokine production by human peripheral blood mononuclear cells of dietary {alpha}-linolenic acid from flaxseed oil and dietary eicosapentaenoic acid from fish oil: 0 wk, baseline; 4 wk, after 4 wk of the flaxseed or sunflower oil diets; 8 wk, after an additional 4 wk of the same diets plus fish-oil supplementation (9 g/d). TNF-{alpha}, tumor necrosis factor {alpha}; IL-1ß, interleukin 1ß. x ± SD; n = 15 for all groups. *Significantly different from baseline value at week 0, P < 0.05. Data are from reference 24.

 
The successful application of any of these dietary approaches to suppressing excessive cytokine production in inflammatory disease rests in our knowledge of the dose-response relations and the mechanisms of action of n-3 fatty acids in the suppression of cytokine production. Regarding the first of these issues, there is an inverse exponential relation between mononuclear cell EPA content and cytokine production. Whether the cellular source of EPA is the diet or endogenous synthesis from dietary ALA, cytokine synthesis decreases as cellular EPA concentrations increase to {approx}1% of total membrane fatty acids. Further increases in EPA content, however, do not result in further measurable decreases in cytokine production (Figure 4Go) (24).



View larger version (15K):
[in this window]
[in a new window]
  		FIGURE 4. . Relation between mononuclear cell eicosapentaenoic acid (EPA) content and cytokine production. Open symbols, sunflower oil diet; closed symbols, flaxseed oil diet; circles, 4 wk of vegetable oil diets; squares, additional 4 wk of the same diets plus fish oil; TNF-{alpha}, tumor necrosis factor {alpha}; IL-1ß, interleukin 1ß. Reproduced with permission from reference 24.

 
The mechanisms responsible for the suppression of cytokine production by n-3 fatty acids remain unknown, although suppression of eicosanoid production by n-3 fatty acids may be involved. Ingestion of n-3 fatty acids leads to suppression of thromboxane A2 (TXA2) synthesis by platelets and by gradient preparations of blood mononuclear cells (24). In the mononuclear cell preparations, the TXA2 is derived from contaminating platelets but also from the monocytes, where it is a major eicosanoid product (26). When TXA2, but not PGE2, synthesis was inhibited in purified human monocytes, TNF-{alpha} and IL-1ß synthesis were inhibited and the inhibition was overcome by the addition of an active TXA2 analogue. Also, cytokine synthesis was inhibited by TXA-receptor antagonists. Collectively, these results provide evidence of a role for TXA2 as an autocrine or paracrine facilitator of cytokine synthesis (26). However, other results suggest that the relation between monocyte eicosanoid and cytokine production probably reflects a balance between the opposing effects of TXA2 and PGE2 (26). Because n-3 fatty acids inhibit PGE2 synthesis also, inhibition of TXA2 synthesis may provide only one element of a complex mechanism responsible for inhibition of cytokine synthesis by n-3 fatty acids.


   DIETARY CONSIDERATIONS
TOP
 ABSTRACT
 INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
FUTURE ROLE OF DIETARY...
 REFERENCES
 
When fortifying diets with either EPA, ETA, or both with therapeutic or health-enhancing intent, the background n-6 PUFA content of the diet is a key issue. The competitive interactions between n-6 and n-3 dietary fatty acids that determine the cellular content of the long-chain, highly unsaturated n-6 and n-3 fatty acids such as AA and EPA have been studied and well described mathematically (5, 27). When competition from the major dietary PUFA, LA, was specifically examined, it was observed that higher tissue concentrations of EPA and ETA occurred when these fatty acids were ingested within diets of lower LA content (16, 28). In at least the United States and Australia, the widespread dietary use of LA-rich oils such as soybean, corn, sunflower, and safflower oils results in intakes of LA at {approx}7–8% of dietary energy (29, 30). Whether n-3 or n-9 fats are considered for use as components of foodstuffs or as dietary supplements, the LA content of the modern Western diet merits attention because of its negative effect on tissue concentrations of n-3 and n-9 fatty acids.


   FUTURE ROLE OF DIETARY POLYUNSATURATED FATTY ACIDS IN THERAPIES FOR INFLAMMATORY DISORDERS
TOP
 ABSTRACT
 INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
REFERENCES
 
A beneficial clinical effect of dietary supplementation with fish oil on rheumatoid arthritis was observed in at least 11 double-blind, placebo-controlled studies, and in the studies in which drug use was examined, there was partial sparing of nonsteroidal antiinflammatory drug use [summarized in references 31 and 32 and discussed in detail by Kremer in this supplement (33)]. Common features of the clinical studies that may have moderated the size of the effects observed were that 1) all studies were conducted against unmodified Western diets, ie, diets high in LA, and 2) the usual antiinflammatory and antirheumatic medications were used in addition to fish oil in amounts likely to confer maximum suppression of their common molecular and cellular targets.

The first issue could be addressed by substituting vegetable oils rich in monounsaturated fatty acids for the current oils rich in LA and, preferably, by also using oils with substantial ALA content. The second issue could be addressed by optimizing the possible additive effects of drug-diet combinations. Antiinflammatory drug use could be decreased in some patients with rheumatoid arthritis in concert with increased fish-oil ingestion if both the drug and fish oil are exerting their therapeutic effects through the same molecular actions, eg, inhibition of PGE2 and TXA2 production. This might also apply to new drugs or new treatment modalities that aim to suppress cytokine concentrations, ie, there may be an opportunity for beneficial additive effects with fish-oil supplementation or any other dietary approach to increasing intake of n-3 fats. Similar arguments apply to use of ETA with drugs that target LTB4 synthesis. Thus, the possibility exists for drug-diet interactions that confer greater antiinflammatory benefits than either agent alone or similar antiinflammatory effects with less toxicity (Figure 5Go). Investigation of potentially beneficial interactions will require greater knowledge of the dose-response effects for both the drug (including biological agent therapies) and the dietary intake of n-3 PUFAs.



View larger version (17K):
[in this window]
[in a new window]
  		FIGURE 5. . Scheme depicting common molecular targets for antiinflammatory therapies that use dietary n-3 fatty acids and pharmaceuticals. PGE2, prostaglandin E2; LTB4, leukotriene B4; TXA2, thromboxane A2; TNF-{alpha}, tumor necrosis factor {alpha}; IL-1ß, interleukin 1ß.

 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 POLYUNSATURATED FATTY ACIDS IN...
 EFFECT OF DIETARY n-3...
 EFFECT OF DIETARY n-3...
 DIETARY CONSIDERATIONS
 FUTURE ROLE OF DIETARY...
 REFERENCES
 

  1. Henderson B, Pettipher ER, Higgs GA. Mediators of rheumatoid arthritis. Br Med Bull 1987;43:415–28.[Abstract/Free Full Text]
  2. Arend WP, Dayer J-M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor {alpha} in rheumatoid arthritis. Arthritis Rheum 1995;38:151–60.[Medline]
  3. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor {alpha} (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344:1105–10.[Medline]
  4. Simopoulos AP. {omega}-3 Fatty acids in health and disease and in growth and development. Am J Clin Nutr 1991;54:438–63.[Abstract/Free Full Text]
  5. Lands WEM, Morris A, Libelt B. Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues. Lipids 1990;25:505–16.[Medline]
  6. Hawkes JS, James MJ, Cleland LG. Biological activity of prostaglandin E3 with regard to oedema formation in mice. Agents Actions 1992;35:85–7.[Medline]
  7. Hawkes JS, James MJ, Cleland LG. Separation and quantification of PGE3 following derivatization with panacyl bromide by high pressure liquid chromatography with fluorometric detection. Prostaglandins 1991;42:355–68.[Medline]
  8. James MJ, Cleland LG, Gibson RA, Hawkes JS. Interaction between fish and vegetable oils in relation to rat leucocyte leukotriene production. J Nutr 1991;121:631–7.
  9. Goldman DW, Pickett WC, Goetzl EJ. Human neutrophil chemotactic and degranulating activities of leukotriene B5 (LTB5) derived from eicosapentaenoic acid. Biochem Biophys Res Commun 1983; 117:282–8.[Medline]
  10. Evans JF, Nathaniel DJ, Zamboni RJ, Ford-Hutchinson AW. Leukotriene A3. A poor substrate but a potent inhibitor of rat and human neutrophil leukotriene A4 hydrolase. J Biol Chem 1985; 260:10966–70.[Abstract/Free Full Text]
  11. Jakschik BA, Morrison AR, Sprecher H. Products derived from 5,8,11-eicosatrienoic acid by the 5-lipoxygenase-leukotriene pathway. J Biol Chem 1983;258:12797–800.[Abstract/Free Full Text]
  12. Stenson WF, Prescott SM, Sprecher H. Leukotriene B formation by neutrophils from essential fatty acid-deficient rats. J Biol Chem 1984;259:11784–9.[Abstract/Free Full Text]
  13. Cleland LG, James MJ, Proudman SM, Neumann MA, Gibson RA. Inhibition of human neutrophil leukotriene B4 synthesis in essential fatty acid deficiency: role of leukotriene A hydrolase. Lipids 1994; 29:151–5.[Medline]
  14. Cleland LG, Neumann MA, Gibson RA, Hamazaki T, Akimoto K, James MJ. Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue phospholipids. Lipids 1996;31:829–37.[Medline]
  15. James MJ, Gibson RA, Neumann MA, Cleland LG. Effect of dietary supplementation with n-9 eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid synthesis. J Exp Med 1993;178:2261–5.[Abstract/Free Full Text]
  16. Cleland LG, Gibson RA, Neumann MA, Hamazaki T, Akimoto K, James MJ. Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic acid. J Nutr 1996;126:1534–40.
  17. Lerner R, Lindstrom P, Berg A, Johansson E, Rosendahl K, Palmblad J. Development and characterization of essential fatty acid deficiency in human endothelial cells. Proc Natl Acad Sci U S A 1995;92:1147–51.[Abstract/Free Full Text]
  18. Dinarello CA. Interleukin-1 and its biologically related cytokines. Adv Immunol 1989;44:153–205.[Medline]
  19. Moser R, Schleiffenbaum B, Groscurth P, Fehr J. Interleukin 1 and tumor necrosis factor stimulate human vascular endothelial cells to promote transendothelial neutrophil passage. J Clin Invest 1989; 83:444–55.
  20. Pettipher ER, Higgs GA, Henderson B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci U S A 1986;83:8749–53.[Abstract/Free Full Text]
  21. Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991;10:4025–31.[Medline]
  22. 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;320:265–71.[Abstract]
  23. Meydani S, Endres S, Woods MM, et al. Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between younger and older women. J Nutr 1991;121:547–55.
  24. Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor necrosis factor {alpha} and interleukin 1ß production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr 1996;63:116–22.[Abstract/Free Full Text]
  25. Kremer JM, Lawrence DA, Jubiz W, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:810–20.[Medline]
  26. Caughey GE, Pouliot M, Cleland LG, James MJ. Regulation of tumor necrosis factor alpha and interleukin-1 beta synthesis by thromboxane A2 in non-adherent human monocytes. J Immunol 1997;158:351–8.[Abstract]
  27. Lands WEM, Libelt B, Morris A, et al. Maintenance of lower proportions of (n-6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n-3) fatty acids. Biochim Biophys Acta 1992;1180:147–62.[Medline]
  28. Cleland LG, James MJ, Neumann MA, D'Angelo M, Gibson RA. Linoleate inhibits EPA incorporation from dietary fish-oil supplements in human subjects. Am J Clin Nutr 1992;55:395–9.[Abstract/Free Full Text]
  29. Lands WEM, Hamazaki T, Yamazaki K, et al. Changing dietary patterns. Am J Clin Nutr 1990;51:991–3.[Abstract/Free Full Text]
  30. Baghurst KI, Crawford DA, Worsley A, Record SJ. The Victorian Nutrition Survey: intakes and sources of dietary fats in the Victorian population. Med J Aust 1988;149:12–20.[Medline]
  31. Cleland LG, Hill CL, James MJ. Diet and arthritis. In: Brooks PM, Furst DE, eds. Bailliere's clinical rheumatology. Innovative treatment approaches for rheumatoid arthritis. Vol 9. London: Bailliere Tindall, 1995:771–85.
  32. James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum 1997;27:85–97.[Medline]
  33. Kremer JM. n-3 Fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000;71(suppl):349S–51S.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Psychosom. Med.Home page
A. A. Amin, R. A. Menon, K. J. Reid, W. S. Harris, and J. A. Spertus
Acute Coronary Syndrome Patients With Depression Have Low Blood Cell Membrane Omega-3 Fatty Acid Levels
Psychosom Med, October 1, 2008; 70(8): 856 - 862.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
O. Poulain-Godefroy, C. Lecoeur, F. Pattou, G. Fruhbeck, and P. Froguel
Inflammation is associated with a decrease of lipogenic factors in omental fat in women
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R1 - R7.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Coll. Nutr.Home page
D. J.A. Jenkins, A. R. Josse, P. Dorian, M. L. Burr, R. LaBelle Trangmar, C. W.C. Kendall, and S. C. Cunnane
Heterogeneity in Randomized Controlled Trials of Long Chain (Fish) Omega-3 Fatty Acids in Restenosis, Secondary Prevention and Ventricular Arrhythmias
J. Am. Coll. Nutr., June 1, 2008; 27(3): 367 - 378.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
F. Biasi, C. Mascia, and G. Poli
The contribution of animal fat oxidation products to colon carcinogenesis, through modulation of TGF-{beta}1 signaling
Carcinogenesis, May 1, 2008; 29(5): 890 - 894.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
C. Song, M. S. Manku, and D. F. Horrobin
Long-Chain Polyunsaturated Fatty Acids Modulate Interleukin-1{beta}-Induced Changes in Behavior, Monoaminergic Neurotransmitters, and Brain Inflammation in Rats
J. Nutr., May 1, 2008; 138(5): 954 - 963.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
S. Rashid, Y. Jin, T. Ecoiffier, S. Barabino, D. A. Schaumberg, and M. R. Dana
Topical Omega-3 and Omega-6 Fatty Acids for Treatment of Dry Eye
Arch Ophthalmol, February 1, 2008; 126(2): 219 - 225.
[Abstract] [Full Text] [PDF]

Home page
 JPEN J Parenter Enteral NutrHome page
Z. Kun, Z. Haiyun, W. Meng, Li Ning, Li Yousheng, and Li Jieshou
Dietary {omega}-3 Polyunsaturated Fatty Acids Can Inhibit Expression of Granzyme B, Perforin, and Cation-Independent Mannose 6-Phosphate/Insulin-Like Growth Factor Receptor in Rat Model of Small Bowel Transplant Chronic Rejection
JPEN J Parenter Enteral Nutr, January 1, 2008; 32(1): 12 - 17.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
E. K. Kabagambe, M. Y. Tsai, P. N. Hopkins, J. M. Ordovas, J. M. Peacock, I. B. Borecki, and D. K. Arnett
Erythrocyte Fatty Acid Composition and the Metabolic Syndrome: A National Heart, Lung, and Blood Institute GOLDN Study
Clin. Chem., January 1, 2008; 54(1): 154 - 162.
[Abstract] [Full Text] [PDF]

Home page
 JPEN J Parenter Enteral NutrHome page
Y. Maeshima, K. Fukatsu, T. Moriya, F. Ikezawa, C. Ueno, D. Saitoh, and H. Mochizuki
Influence of Adding Fish Oil to Parenteral Nutrition on Gut-Associated Lymphoid Tissue
JPEN J Parenter Enteral Nutr, September 1, 2007; 31(5): 416 - 422.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Coll. Nutr.Home page
Y. Miyake, S. Sasaki, K. Tanaka, Y. Ohya, S. Miyamoto, I. Matsunaga, T. Yoshida, Y. Hirota, H. Oda, and the Osaka Maternal and Child Health Study Group
Fish and Fat Intake and Prevalence of Allergic Rhinitis in Japanese Females: the Osaka Maternal and Child Health Study
J. Am. Coll. Nutr., June 1, 2007; 26(3): 279 - 287.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
E. M. Poole, J. Bigler, J. Whitton, J. G. Sibert, R. J. Kulmacz, J. D. Potter, and C. M. Ulrich
Genetic variability in prostaglandin synthesis, fish intake and risk of colorectal polyps
Carcinogenesis, June 1, 2007; 28(6): 1259 - 1263.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
A. M Hill, J. D Buckley, K. J Murphy, and P. R. Howe
Combining fish-oil supplements with regular aerobic exercise improves body composition and cardiovascular disease risk factors
Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1267 - 1274.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
G. Zhao, T. D Etherton, K. R Martin, P. J Gillies, S. G West, and P. M Kris-Etherton
Dietary {alpha}-linolenic acid inhibits proinflammatory cytokine production by peripheral blood mononuclear cells in hypercholesterolemic subjects
Am. J. Clinical Nutrition, February 1, 2007; 85(2): 385 - 391.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
A. Baylin, E. Ruiz-Narvaez, P. Kraft, and H. Campos
{alpha}-Linolenic acid, {Delta}6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction
Am. J. Clinical Nutrition, February 1, 2007; 85(2): 554 - 560.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Coll. Nutr.Home page
L. Deutsch
Evaluation of the Effect of Neptune Krill Oil on Chronic Inflammation and Arthritic Symptoms
J. Am. Coll. Nutr., February 1, 2007; 26(1): 39 - 48.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
R. Fiaccavento, F. Carotenuto, M. Minieri, L. Masuelli, A. Vecchini, R. Bei, A. Modesti, L. Binaglia, A. Fusco, A. Bertoli, et al.
{alpha}-Linolenic Acid-Enriched Diet Prevents Myocardial Damage and Expands Longevity in Cardiomyopathic Hamsters
Am. J. Pathol., December 1, 2006; 169(6): 1913 - 1924.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
A. A. Farooqui, W.-Y. Ong, and L. A. Horrocks
Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders
Pharmacol. Rev., September 1, 2006; 58(3): 591 - 620.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Xia, Y. Lu, J. Wang, C. He, S. Hong, C. N. Serhan, and J. X. Kang
Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids
PNAS, August 15, 2006; 103(33): 12499 - 12504.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. A. Hudert, K. H. Weylandt, Y. Lu, J. Wang, S. Hong, A. Dignass, C. N. Serhan, and J. X. Kang
Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis
PNAS, July 25, 2006; 103(30): 11276 - 11281.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
K. Niu, A. Hozawa, S. Kuriyama, K. Ohmori-Matsuda, T. Shimazu, N. Nakaya, K. Fujita, I. Tsuji, and R. Nagatomi
Dietary long-chain n-3 fatty acids of marine origin and serum C-reactive protein concentrations are associated in a population with a diet rich in marine products
Am. J. Clinical Nutrition, July 1, 2006; 84(1): 223 - 229.
[Abstract] [Full Text] [PDF]

Home page
 Crop Sci.Home page
R. Scarth and J. Tang
Modification of Brassica Oil Using Conventional and Transgenic Approaches
Crop Sci., April 25, 2006; 46(3): 1225 - 1236.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
C. J. Boos, R. A. Anderson, and G. Y.H. Lip
Is atrial fibrillation an inflammatory disorder?
Eur. Heart J., January 2, 2006; 27(2): 136 - 149.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
C. H MacLean, W. A Mojica, S. J Newberry, J. Pencharz, R. H. Garland, W. Tu, L. G Hilton, I. M Gralnek, S. Rhodes, P. Khanna, et al.
Systematic review of the effects of n-3 fatty acids in inflammatory bowel disease
Am. J. Clinical Nutrition, September 1, 2005; 82(3): 611 - 619.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
D. Mozaffarian, C. L. Bryson, R. N. Lemaitre, G. L. Burke, and D. S. Siscovick
Fish Intake and Risk of Incident Heart Failure
J. Am. Coll. Cardiol., June 21, 2005; 45(12): 2015 - 2021.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
L. Djousse, D. K. Arnett, J. J. Carr, J. H. Eckfeldt, P. N. Hopkins, M. A. Province, and R. C. Ellison
Dietary Linolenic Acid Is Inversely Associated With Calcified Atherosclerotic Plaque in the Coronary Arteries: The National Heart, Lung, and Blood Institute Family Heart Study
Circulation, June 7, 2005; 111(22): 2921 - 2926.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
C. J McNeil, A. M Finch, K. R Page, S. D Clarke, C. J Ashworth, and H. J McArdle
The effect of fetal pig size and stage of gestation on tissue fatty acid metabolism and profile
Reproduction, June 1, 2005; 129(6): 757 - 763.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
R. Geyeregger, M. Zeyda, G. J. Zlabinger, W. Waldhausl, and T. M. Stulnig
Polyunsaturated fatty acids interfere with formation of the immunological synapse
J. Leukoc. Biol., May 1, 2005; 77(5): 680 - 688.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
R. Irons, P. Pinge-Filho, and K. L. Fritsche
Dietary (n-3) Polyunsaturated Fatty Acids Do Not Affect the In Vivo Development and Function of Listeria-Specific CD4+ and CD8+ Effector and Memory/Effector T Cells in Mice
J. Nutr., May 1, 2005; 135(5): 1151 - 1156.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
E. M Hjerkinn, I. Seljeflot, I. Ellingsen, P. Berstad, I. Hjermann, L. Sandvik, and H. Arnesen
Influence of long-term intervention with dietary counseling, long-chain n-3 fatty acid supplements, or both on circulating markers of endothelial activation in men with long-standing hyperlipidemia
Am. J. Clinical Nutrition, March 1, 2005; 81(3): 583 - 589.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
C. L.E. Siezen, A. I.M. van Leeuwen, N. R. Kram, M. E.M. Luken, H. J. van Kranen, and E. Kampman
Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption
Carcinogenesis, February 1, 2005; 26(2): 449 - 457.
[Abstract] [Full Text] [PDF]