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ORIGINAL RESEARCH COMMUNICATION |
1 From the Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, United Kingdom.
2 The capsules used in the study were a gift from Ocean Nutrition (Bedford, Canada). MDM was supported by a postdoctoral fellowship from the University of Granada (Spain) and the Ministry of Spain. 3 Address reprint requests to P Yaqoob, Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, Whiteknights, Reading RG6 6AP, United Kingdom. E-mail: p.yaqoob{at}reading.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: The objective of the study was to determine the effects of supplementation with an EPA-rich or DHA-rich oil on a range of immune outcomes representing key functions of human neutrophils, monocytes, and lymphocytes in healthy humans.
Design: In a placebo-controlled, double-blind, parallel study, 42 healthy subjects were randomly allocated to receive supplementation with either placebo (olive oil), EPA (4.7 g/d), or DHA (4.9 g/d) for 4 wk. Blood samples were taken before and after supplementation.
Results: The fatty acid composition of plasma phospholipids and neutrophils was dramatically altered by supplementation with EPA or DHA, and the effects of EPA differed notably from those of DHA. DHA supplementation decreased T lymphocyte activation, as assessed by expression of CD69, whereas EPA supplementation had no significant effect. Neither the EPA-rich oil nor the DHA-rich oil had any significant effect on monocyte or neutrophil phagocytosis or on cytokine production or adhesion molecule expression by peripheral blood mononuclear cells.
Conclusions: Supplementation with DHA, but not with EPA, suppresses T lymphocyte activation, as assessed by expression of CD69. EPA alone does not, therefore, influence CD69 expression. No other marker of immune function assessed in this study was significantly affected by either EPA or DHA.
Key Words: Docosahexaenoic acid • eicosapentaenoic acid • fish oil • immunity • inflammation • lymphocytes • monocytes • polyunsaturated fatty acids
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animal studies tend to suggest that both EPA and DHA have immunomodulatory effects. Both EPA and DHA fed to rats at 4.4 g/100 g total fatty acids inhibited lymphocyte proliferation, although only EPA inhibited NK cell activity (2). In a study conducted in mice, both EPA and DHA suppressed the proliferation and production of interleukin 2 (IL-2) by splenic lymphocytes (3). However, 2 animal models of inflammation showed different effects of EPA and DHA: one model suggested reduced inflammation with DHA (4), whereas the other model suggested that EPA is more antiinflammatory than is DHA (5).
Only one study to date directly compared the effects of EPA and DHA on immune function in humans. In that study, a comparison of the effects of 3.8 g EPA/d or 3.6 g DHA/d with those of a control treatment of linoleic acid showed no differential effects of the n-3 PUFAs on the phagocytic activity of monocytes (6). Other human studies have ascribed an immunomodulatory action to either EPA or DHA on the basis of indirect evidence. For example, Thies et al (7) compared the effects of supplementation with fish oil, highly purified DHA, or a placebo on lymphocyte proliferation in healthy subjects and showed that fish oil suppresses lymphocyte proliferation whereas DHA has no effect. This could be taken to suggest either that EPA is responsible for the inhibitory effect or that both EPA and DHA are required. In the same study, fish oil, but not DHA, decreased NK cell activity (8). One further study examined the immunomodulatory effect of DHA alone. Kelley et al (9, 10) examined the effects of 6 g DHA/d, which replaced 20% of dietary linoleic acid, on several immune responses. They reported no effect of DHA on lymphocyte proliferation, production of IL-2, antibody production, or delayed type hypersensitivity (9). In contrast, DHA did appear to decrease NK cell activity and production of the inflammatory cytokines tumor necrosis factor-
(TNF-) and IL-1ß (10). Given the continued interest in the immunomodulatory effects of n-3 PUFAs and the lack of clarity regarding the differential effects of EPA and DHA, the aim of the present study was to directly compare the effects of EPA and DHA with those of a control treatment on the fatty acid composition of immune cells and on a wide range of ex vivo immune cell responses.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Subjects and study design
Ethical permission for all procedures involving human volunteers was obtained from the University of Reading Ethics and Research Committee and the West Berkshire Health Authority Ethics Committee. Healthy adults aged 23–65 y were invited to participate in the study. Volunteers were excluded if they were taking any prescribed antiinflammatory medication; had diagnosed cardiovascular disease, diabetes, liver or endocrine dysfunction, or chronic inflammatory disease; were pregnant or lactating; were vegetarian; consumed fish oil, evening primrose oil, or vitamin supplements; smoked > 15 cigarettes/d; exercised strenuously > 3 times/wk; had a body mass index (in kg/m2) < 20 or > 32; or consumed > 2 portions of oily fish/wk. Forty-two subjects were recruited for the study and were randomly allocated to 1 of 3 intervention groups (n = 14–15 per treatment group); randomization was stratified by age, body mass index, and fasting plasma triacylglycerol concentration (due to the well-documented triacylgycerol-lowering effects of fish oil). The mean (± SEM) age (44.8 ± 14.4, 46.1 ± 13.3, and 45.3 ± 14.6 y in the placebo, EPA, and DHA groups, respectively) and body mass index (25.8 ± 2.6, 25.9 ± 4.3, and 25.0 ± 2.3 in the placebo, EPA, and DHA groups, respectively) did not differ significantly between the treatment groups.
Each subject was asked to consume 9 oil capsules/d (three 1-g capsules with each main meal). Each capsule contained 1 g olive oil (placebo), 1 g of an EPA-enriched fish oil, or 1 g of a DHA-enriched fish oil. The EPA-enriched and DHA-enriched oils were supplemented with 10 IU mixed natural tocopherols/capsule to prevent oxidation. The fatty acid composition of the oils is shown in Table 1
. From the capsules, the EPA group consumed 4.75 g EPA/d plus 0.73 g DHA/d, whereas the DHA group consumed 0.85 g EPA/d plus 4.91 g DHA/d.
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Preparation of peripheral blood mononuclear cells and neutrophils
Blood samples were collected in heparinized, evacuated tubes between 0800 and 1000 after the subjects had fasted 
10 h. The blood was layered onto Histopaque (density, 1.077 g/L; ratio of blood to Histopaque, 1:1) and centrifuged for 15 min at 800 x g and 20 °C. The cells [termed peripheral blood mononuclear cells (PBMCs)] were collected from the interface and washed once with RPMI medium containing 0.75 mmol glutamine/L and antibiotics (penicillin and streptomycin) (culture medium). After resuspension in 4 mL culture medium, the cells were layered onto 4 mL Histopaque. They were centrifuged once more (15 min, 800 x g, 20 °C) to achieve a lower degree of erythrocyte contamination, washed with culture medium, resuspended, and finally counted on a Coulter Z1 Cell Counter (Beckman Coulter Ltd, Bucks, United Kingdom).
Neutrophils were prepared by collecting the white blood cell layer directly above the erythrocytes in the first Histopaque step described above and by removing contaminating erythrocytes by lysing with EDTA (37.2 mg/L), NH4CL (8.29 g/L), and KHCO3 (1 g/L). Neutrophils were washed with phosphate-buffered saline and stored at -20 °C for fatty acid analysis.
Analysis of monocyte adhesion molecules
For the determination of expression of monocyte adhesion molecules, whole blood (100 µL) was incubated with various fluorescently labeled monoclonal antibodies for 30 min at 4 °C. The monoclonal antibodies included anti-CD54 (intercellular adhesion molecule 1), anti-CD49d (component of very late antigen 4), anti-CD11b (Mac-1), and anti-CD18 (ß chain of leukocyte function-associated antigen 1). Erythrocytes were then lysed by using 2 mL lysing solution (Becton Dickinson), and leukocytes were washed and fixed with 0.2 mL FACSFix solution (Becton Dickinson). Fixed leukocytes were analyzed in a Becton Dickinson FACSCalibur flow cytometer (Becton Dickinson). Fluorescence data were collected from 2 x 104 cells and analyzed by using CELLQUEST software (Becton Dickinson).
Analysis of fatty acid composition of plasma phospholipids and of total lipids in neutrophils
Lipid was extracted from plasma and neutrophils with chloroform:methanol (2:1, by vol). Plasma phospholipids were isolated by using thin layer chromatography with hexane:diethyl ether:acetic acid (90:30:1, by vol) as the elution phase. Fatty acid methyl esters were prepared by incubation with 140 g BF3/L in methanol at 80 °C for 60 min. Fatty acid methyl esters were reextracted into hexane and analyzed in a gas chromatograph (model 6890; Hewlett-Packard, Avondale, PA) fitted with a 50-m x 0.25-mm Chrompack 6173 fused silica capillary column with a film thickness of 0.25 µm (SGE Europe Ltd, Milton Keynes, Bucks, United Kingdom). Helium was used as the carrier gas at a flow rate of 2.4 mL/min, and a split-splitless injector was used with a split-splitless ratio of 15:1. Injector and detector temperatures were 240 and 250 °C, respectively. The oven temperature was programmed to increase from 100 to 240 °C in increments of 4 °C/min and then remain at 240 °C for 4 min. The separation was recorded with HP CHEMSTATION software (Hewlett-Packard). Fatty acid methyl esters were identified by comparison with standards run previously.
Measurement of phagocytic activity
Phagocytosis by neutrophils and monocytes was determined by using Phagotest kits. Before use, blood was cooled on ice for 10 min and then mixed by vortex for 5 s. Aliquots (100 µL) of blood were incubated on ice (control) or in a preheated water bath at 37 °C for 10 min with opsonized fluorescein isothiocyanate-labeled E. coli (20 µL). The reaction was stopped by adding ice-cold quenching solution (100 µL). At the completion of phagocytosis incubation, erythrocytes were lysed, leukocytes were fixed, and the DNA was stained according to the manufacturer’s instructions. Cell preparations were then analyzed by using flow cytometry with a Becton Dickinson FACSCalibur flow cytometer. Fluorescence data were collected from 2 x 104 cells and analyzed by using CELLQUEST software. Neutrophils and monocytes were identified by forward and side scatter. Both the percentage of neutrophils or monocytes engaging in phagocytosis (percent positive) and the median fluorescence intensity (MFI, a measure of the extent of phagocytosis) were determined.
Measurement of T lymphocyte activation in whole blood
Lymphocyte activation was determined by measurement of the expression of CD69 (a cell surface marker for which expression is rapidly upregulated in response to stimulation). Before use, blood was diluted 1:1 with culture medium and then cultured for 24 h with Con A at a final concentration of 0, 6.25, 12.5, or 25 mg/L; the final volume of the culture was 250 µL. For the determination of CD69 expression on lymphocytes, the stimulated, diluted whole blood (200 µL) was incubated with fluorescently labeled monoclonal antibodies for 30 min at 4 °C. The monoclonal antibodies were anti-CD69 and anti-CD3 (to distinguish T lymphocytes). At the completion of incubation, the erythrocytes were lysed, and the leukocytes were fixed. Cell preparations were then analyzed by using flow cytometry with a Becton Dickinson FACSCalibur flow cytometer. Fluorescence data were collected from 2 x 104 cells and analyzed by using CELLQUEST software. Lymphocytes were identified as being CD3+, and both the percentage of lymphocytes expressing CD69 (percentage positive) and the MFI (related to the number of CD69 molecules expressed per T lymphocyte) were determined.
Measurement of cytokine production by PBMC cultures
PBMCs (1 x 106) were cultured for 24 h in culture medium supplemented with 50 mL autologous plasma/L and either 25 mg Con A/L or 15 mg lipopolysaccharides/L; the final culture volume was 1 mL. At the end of the incubation, the plates were centrifuged for 10 min at 400 x g and room temperature, and the culture medium was collected and frozen in aliquots. The concentrations of cytokines were measured by using flow cytometry with cytometric bead arrays (Becton Dickinson). TNF-, IL-1ß, IL-6, IL-8, and IL-10 were measured in the supernatant fluids of cells stimulated with lipopolysaccharides, and IL-2, interferon-
(IFN-), IL-10, IL-5, TNF-, and IL-4 were measured in the supernatant fluids of cells stimulated with Con A. The limits of detection for these assays were as follows: IL-8, 3.6 ng/mL; TNF-, 3.7 ng/L; IL-1ß, 7.2 ng/L; IL-6, 2.5 ng/mL; IL-10, 3.3 ng/L; IL-4, 2.6 ng/mL; IL-2, 2.6 ng/mL; IL-5, 2.4 ng/mL; and IFN-, 7.1 ng/mL (data were supplied by the manufacturer of the kits). The inter- and intra-assay CVs were < 10% for all cytokine bead arrays.
Statistical analysis
For data that were normally distributed (Shapiro-Wilk test), a two-factor repeated-measures analysis of variance (ANOVA) with post hoc Tukey test was used to determine effects of treatment and time and their interaction. For the T lymphocyte activation data, three-factor repeated-measures ANOVA was performed, and the factors were time, treatment, and Con A concentration. For all data, a one-factor ANOVA was used to test for significant differences between the groups at baseline. The fatty acid composition data (plasma phospholipids and neutrophils) were log transformed to achieve a normal distribution before statistical analysis was applied. The data showing a change from baseline in CD69 expression after each treatment were analyzed by two-factor repeated-measures ANOVA, and the factors were treatment and Con A concentration. All statistical tests were performed by using SPSS version 11.0 (SPSS Inc, Chicago), and P < 0.05 was taken to indicate statistical significance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-linolenic acid, EPA, docosapentaenoic acid (DPA, 22:5n-3), and DHA (Table 2). The proportion of dihomo--linolenic acid after supplementation in both the EPA and DHA groups was significantly lower than that in the placebo group and significantly lower than the respective baseline values. The proportion of EPA in plasma phospholipids in both the EPA and DHA groups was significantly higher than that in the placebo group, but the proportion of EPA in the EPA group was significantly higher than that in the DHA group. The proportion of DPA in the EPA group was significantly higher than that in the placebo and DHA groups. Finally, the proportion of DHA in plasma phospholipids in the DHA group was significantly higher than that in the EPA and placebo groups.
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). As with the plasma phospholipids, the proportion of EPA after supplementation in both the EPA and DHA groups was significantly higher than that in the placebo group, but the proportion of EPA in the EPA group was significantly higher than that in the DHA group. The proportion of DPA in the EPA group was significantly higher than that in the placebo and DHA groups. Finally, the proportion of DHA in neutrophil lipids in the DHA group was significantly higher than that in the EPA and placebo groups. The overall effects of the treatments on the fatty acid composition of neutrophil lipids were therefore very similar to those on the plasma phospholipids, apart from a lack of significant change in the proportion of DGLA.
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. Three-factor ANOVA showed a significant effect of Con A on both the percentage of CD69-positive cells (P < 0.001) and on CD69 MFI (P < 0.001). Mitogenic stimulation of whole blood cultures therefore resulted in increased expression of the early activation marker CD69 on T lymphocytes. The percentage of cells expressing CD69 increased with increasing concentrations of Con A, whereas CD69 MFI, which reflects the level of activation on a per cell basis, reached a plateau at the lowest concentration of 6 mg Con A/L. Although there was no effect of treatment on T lymphocyte activation when expressed as a percentage of CD69-positive cells, there was a significant treatment effect for expression of CD69 (P < 0.05). The change in MFI from baseline for each of the treatment groups is shown in Figure 1. There was a significant effect of treatment (P < 0.01), but not of Con A concentration, on the change in CD69 MFI from baseline, as analyzed by two-factor repeated-measures ANOVA. Because there was no treatment x Con A concentration interaction, no further statistical analysis was conducted. However, on the basis of the results shown in Figure 1, DHA treatment appeared to decrease CD69 MFI from the baseline value, whereas EPA did not, because the marginal mean for the DHA group was significantly different from that for the placebo group and the EPA group. The marginal means for the placebo and EPA groups, in contrast, were not significantly different from one another.
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. There was no effect of treatment or time on any of these variables of phagocytosis in either neutrophils or monocytes. In addition, none of the treatments had a significant effect on the expression of adhesion molecules by monocytes (Table 6).
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, IL-10, IL-6, IL-1ß, and IL-8) are shown in Table 7, and the effects on the production of lymphocyte-derived T helper 1 and T helper 2 cytokines (IFN-, TNF-, IL-10, IL-5, IL-4, and IL-2) are shown in Table 8. There were no significant effects of time or treatment on the production of any of these cytokines. However, this data showed a high degree of intersubject variation. As a result, although there was a trend toward a decrease in the production of IFN- and IL-2 after supplementation with EPA, but not with DHA, this trend was not significant (Tables 7 and 8).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The issue of the potentially different immunomodulatory properties of EPA and DHA is one that, to date, has not been adequately investigated and is clearly important given the variation in the ratio of EPA to DHA in fish-oil preparations. There was no significant effect of either the EPA or the DHA treatment on the expression of the early T lymphocyte activation marker CD69 when expressed as a percentage of CD69-positive cells. However, there was a main effect of treatment group on CD69 MFI. In addition, there was a significant effect of treatment on the change in CD69 MFI from baseline, whereby DHA tended to decrease CD69 MFI from the baseline value, whereas EPA did not. This observation does not appear to be consistent with the lack of effect of DHA on lymphocyte proliferation reported by Thies et al (7) or Kelley et al (9). However, both of these studies assessed markers of cell division, whereas the present study assessed the expression of CD69. Although the percentage of CD69-positive cells correlates with the extent of lymphocyte proliferation at different concentrations of mitogen, MFI does not. In the present study, the DHA treatment did not affect the percentage of cells that were CD69 positive. It could therefore be argued that cell division would not have been affected by DHA, which would be consistent with the reported effects of Thies et al (7) and Kelley et al (9). However, DHA treatment did affect the change from baseline in staining intensity of CD69, which suggests a lower expression of CD69 on the cell surface and therefore a lower level of activation of the lymphocyte population. Because the function of CD69 is unknown, the implications of this effect are unclear, but the possibility remains that DHA could affect lymphocyte function without altering proliferation.
The mechanisms responsible for the differential effects of EPA and DHA on T lymphocyte activation are unclear. Recent studies suggested that n-3 PUFAs alter lymphocyte activation by displacing specific signaling proteins from lipid rafts (15). EPA and DHA may conceivably have different effects on raft stability, because DHA is thought to adopt a more folded conformation in membranes and has been shown to exclude phospholipase D from lipid rafts at relatively low concentrations (16). However, it is difficult to predict whether this phenomenon is of physiologic relevance in humans.
The present study showed that there were no significant effects of either EPA or DHA on the expression of monocyte adhesion molecules, which play a role in the adhesion of monocytes to endothelial cells or the extracellular matrix. Although several animal studies suggest that n-3 PUFAs decrease the expression of adhesion molecules on monocytes, evidence in humans is limited (see reference 1 for references). The present study also showed that neither EPA nor DHA had a significant effect on phagocytosis by neutrophils or monocytes, which confirms the observations made by Halvorsen et al (6).
Finally, neither EPA nor DHA had a significant effect on the production of monocyte- and lymphocyte-derived cytokines, although there was a trend toward a decrease in the production of IFN- and IL-2 by lymphocytes in subjects in the EPA group but not in the DHA group. This is not consistent with the results of the study by Kelley et al (10), who reported that supplementation with DHA decreased the production of TNF- and IL-1ß by PBMCs. However, in that study, subjects were supplemented with 6 g DHA/d for 90 d, and thus the dosage and period of supplementation were substantially greater than those used in the present study. There has been considerable inconsistency in the reported effects of n-3 PUFAs on ex vivo production of inflammatory cytokines, and this inconsistency was thought to be due to differences in administered doses (see reference 17). However, this does not fully account for the inconsistency because some studies using high doses of n-3 PUFAs showed no effect on cytokine production, whereas others using low doses reported inhibition (see reference 19 for references). Mantzioris et al (18) adopted the novel approach of setting target tissue EPA concentrations rather than target dietary intakes; they aimed to increase the mononuclear cell EPA content to 1.5% of total fatty acids by 2 wk of dietary modification. The strategy was based on the observation by Caughey et al (19) that the EPA content of mononuclear cells is strongly associated with ex vivo production of IL-1ß and TNF- and that 1.5% EPA in PBMCs results in maximum suppression of cytokine synthesis. However, this does not adequately explain the discrepancies in the literature (20–22). The degree of variation in cytokine production between subjects is considerable, and the data presented in the present study suggest that, given this degree of variation, only a very large effect would be detectable in a study of this size. Thus, many studies investigating the effect of fish oil on cytokine production may have based their power estimates on those of earlier studies that were flawed in design, and therefore the later studies failed to reproduce the effects observed in the earlier studies (23). A reevaluation of this area is clearly necessary.
In summary, supplementation with EPA- or DHA-rich oil had no significant effect on phagocytosis by monocytes or neutrophils or on the expression of adhesion molecules, which is largely consistent with the available data on the effects of fish oils. Neither the EPA-rich oil nor the DHA-rich oil had a significant effect on the production of cytokines by PBMCs, but, because of inconsistency in the literature, this result is difficult to relate to the results of studies investigating the effects of fish oils on cytokine production. Finally, the present study shows that the DHA-rich oil, but not the EPA-rich oil, reduces the expression of an early marker of T lymphocyte activation. Although this appears to contradict some previous reports of a lack of effect of DHA on lymphocyte proliferation, we suggest that DHA may affect lymphocyte function without altering proliferation and that characterization of the effects of EPA and DHA on early signaling processes and on lymphocyte functions other than proliferation will clarify this.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-linolenic acid metabolism in young men. Br J Nutr2002;88:355–63.[Medline]
and interleukin 1ß production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr1996;63:116–22.-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions. Eur J Clin Invest2000;30:260–74.[Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), 6.25 (
), 12.5 (
), or 25 (
) mg/L. The monoclonal antibodies used were anti-CD69 and anti-CD3 (to distinguish T lymphocytes). Cell preparations were analyzed by using flow cytometry, and fluorescence data were collected from 2 x 104 cells. There was a significant main effect of treatment (P < 0.01, two-factor repeated-measures ANOVA) but no effect of Con A concentration and no significant treatment x Con A interaction. The marginal mean for the docosahexaenoic acid (DHA) group was significantly different from that for the placebo group and the eicosapentaenoic acid (EPA) group (P < 0.005 and P < 0.05, respectively; Tukey’s test).