![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Faculty of Nutrition, Molecular and Cell Biology Group and * Department of Medical Microbiology and Immunology, College of Medicine, Texas A&M University, College Station, TX 77843
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGMENTS
LITERATURE CITED
ABSTRACT 
Elucidation of the mechanism(s) by which dietary fish oil, enriched in eicosapentaenoic acid [EPA, 20:5(n-3)] and docosahexaenoic acid [DHA, 22:6(n-3)], suppresses the inflammatory process is essential in maximizing this potentially therapeutic effect. Murine T-lymphocyte function and signal transduction were examined in response to a low fat, short term diet enriched in highly purified EPA or DHA ethyl esters. For 10 d, mice were fed comparable diets containing either 3% safflower oil ethyl esters (SAF), 2% SAF + 1% arachidonic acid triglyceride (AA), 2% SAF + 1% EPA, or 2% SAF + 1% DHA. Concanavalin A-induced T-lymphocyte proliferation in splenocyte cultures was significantly suppressed by dietary EPA and DHA while AA had no effect relative to the SAF control. The suppressed proliferative response in EPA- and DHA-fed mice was preceded temporally by a significant reduction in IL-2 secretion. Kinetics of mitogen-induced diacyl-sn-glycerol (DAG) and ceramide production did not differ significantly between SAF and AA diet groups. In contrast, DAG production was significantly suppressed in EP- and DHA-fed mice relative to the SAF and AA groups. The reduced DAG mass was paralleled by reduced ceramide mass following EPA and DHA feeding compared to the SAF and AA groups. Thus, low dose, short term dietary exposure to highly purified EPA or DHA appears to suppress mitogen-induced T-lymphocyte proliferation by inhibiting IL-2 secretion, and these events are accompanied by reductions in the production of essential lipid second messengers, DAG and ceramide.
Key words: ceramide, diacylglycerol, (n-3) polyunsaturated fatty acids, T-cell, mice.INTRODUCTION
Decreased incidence of inflammatory diseases in Greenland Eskimos and Japanese people (Simopoulos 1991
) has been attributed to their larger consumption of cold-water marine fish, enriched in eicosapentaenoic acid [EPA5 20:5(n-3)] and docosahexaenoic acid [DHA, 22:6(n-3)], relative to the Western diet. Clinical trials involving rheumatoid arthritis (RA) patients have shown that dietary fish oil supplementation has a therapeutic, anti-inflammatory effect (Endres et al. 1995, Kremer 1991). Experiments in rodent models of RA have also demonstrated the beneficial effects of fish oil supplementation (Morrow et al. 1993).
The T-lymphocyte is responsible for propagating both humoral and cell-mediated immunity via proliferation and subsequent secretion of a plethora of lymphokines, including interleukin-2 (IL-2), IL-4, IL-5, IL-6, etc. Dietary fish oil supplementation suppresses the T-lymphocyte proliferative response in vitro of cells from healthy humans, associated with decreased production of IL-2, a potent autocrine and paracrine T-lymphocyte growth factor (Endres et al. 1993). Most of the supplementation studies have employed large amounts of fish oil taken daily in fish oil capsules. However, another human study has shown that the incorporation of fish in the diet suppresses the delayed-type hypersensitivity (DTH) response, a T-lymphocyte dependent phenomenon, and T-lymphocyte proliferative response in vitro (Meydani et al. 1993). That study demonstrated that the anti-inflammatory properties of fish oil can be realized directly by increased fish consumption. Suppressed mitogen-induced T-lymphocyte proliferation was also observed in fish oil-fed rats (Vallette et al. 1991) and mice (Shapiro et al. 1994).
It is essential that the mechanism(s) by which dietary fish oil suppresses the immune response be elucidated in order to maximize the potential therapeutic anti-inflammatory effects without compromising important antimicrobial or antitumor immune system functions. One possible mechanism is that dietary fish oil suppresses prostaglandin (PG) formation. Dietary EPA and DHA suppress arachidonic acid- [AA, 20:4(n-6)] derived PGE2 production (Surette et al. 1995). However, PGE2 is itself an anti-proliferative agent for T-lymphocytes (Hwang 1989); therefore, this putative mechanism is not consistent with the suppressed T-lymphocyte proliferation observed with increased dietary EPA and DHA. Another possible explanation is that EPA and DHA influence the generation of intracellular lipid second messengers. Diacylglycerol (DAG), the physiological activator of protein kinase C, and ceramide, a novel intracellular second messenger, appear to promote T-lymphocyte proliferation (Mathias et al. 1993, Szamel and Resch 1995). DAG is produced by the receptor-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidylcholine (PC) while ceramide is derived from sphingomyelin (SM). We have previously demonstrated that DAG is produced in a multiphasic fashion, and that ceramide exhibits a single, transient, prolonged peak in murine T-lymphocytes stimulated with concanavalin A (Con A) (Jolly et al. 1996), indicating that both DAG and ceramide play important roles in T-lymphocyte proliferation in our model system. Dietary cod liver oil, enriched in EPA and DHA, modifies the fatty acid composition of phosphatidylinositol (PI), PC and SM (Ahmed and Holub 1984). This could affect DAG and ceramide function by altering the hydrolysis of PI, PC and/or SM, yielding lower intracellular DAG and/or ceramide mass and/or influencing effector functions. Alternatively, dietary polyunsaturated fatty acids could modify lymphocyte membrane fluidity resulting in altered receptor function that could influence the generation of intracellular second messengers (Hagve 1988). Furthermore, dietary fish oil could modify the relative proportion of CD4+ or CD8+ T-cells. While fish oil has been shown to alter total spleen cell yield in mice (Fritsche and Johnston 1990), feeding purified EPA (DHA was not tested) to humans resulted in no difference in helper or suppressor T-cells (Payan et al. 1986). The later observation is in agreement with the study showing no change in blood leucocytes in rats fed fish oil (Yaqoob et al. 1995).
We have already shown that both dietary EPA and DHA enhance the (n-3) fatty acid composition of cellular DAG in murine splenocytes (Hosack-Fowler et al. 1993a). Our data clearly demonstrated that both EPA and DHA suppress the DTH response (Hosack-Fowler et al. 1993b) paralleling observations in human studies (Meydani et al. 1993). Furthermore, both EPA and DHA were incorporated into purified splenic T-lymphocyte cellular lipids (Hosack-Fowler et al. 1993b) suggesting that these fatty acids can modulate T-lymphocyte function in our murine model. In this study we extend these observations by demonstrating that dietary EPA and DHA significantly reduce Con A-induced T-lymphocyte proliferation, in part by affecting IL-2 production, and that T-cell suppression is accompanied by significant reductions in T-cell DAG and ceramide mass.
MATERIALS AND METHODS
80°C. The four diet groups varied by lipid source: 30 g/kg SAF (control), 20 g/kg SAF + 10 g/kg AA, 20 g/kg SAF + 10 g/kg EPA, and 20 g/kg SAF + 10 g/kg DHA. The AA diet served as an additional control to determine whether (n-3) fatty acid effects were due to EPA and/or DHA substitution or to reduced dietary linoleic acid [18:2(n-6)] content. The SAF, EPA and DHA were obtained in ethyl ester form, and the AA was provided in triglyceride form. All ethyl esters were obtained from the National Institutes of Health Test Materials Program (Charleston, SC), and the AA was from Martek (Columbia, MD). The EPA was 99% 20:5(n-3), the DHA was 97% 22:6(n-3), the SAF was 84% 18:2(n-6), and the AA was 51.4% 20:4(n-6).
Isolation and preparation of splenic lymphocytes.
Mice were killed by CO2 asphyxiation, and each spleen was placed in 3 mL of complete medium [RPMI 1640 with 25 mmol/L HEPES (Irvine Scientific, Santa Ana, CA) supplemented with 10% fetal bovine serum (FBS) (Irvine Scientific), 1 × 105 U/L penicillin and 100 mg/L streptomycin (Irvine Scientific), 2 mmol/L L-glutamine, and 10 mmol/L 2-mercaptoethanol]. Spleens were dispersed using glass homogenizers, passed through a wire mesh filter to obtain a single cell suspension that was washed twice with complete medium. The number of viable cells was determined by trypan blue exclusion in a hemocytometer (Hosack-Fowler et al. 1993b).
T-lymphocyte proliferation assay.
Splenic lymphocytes were cultured in the presence of 5 mg/L of the T cell mitogenic lectin Con A (Sigma, St. Louis, MO) at 2 × 105 cells per well in 96-well flat bottomed microtiter plates (Falcon; Becton Dickenson, Lincoln Park, NJ), with triplicate wells for each diet treatment. Cells were incubated for 96 h at 37°C in a 5% CO2 in air atmosphere. For the final 6 h, cells were incubated in the presence of 37 kBq [3H]-thymidine/well (New England Nuclear, North Bellerica, MA). Cells were harvested onto glass fiber filter paper discs (Whatman, Maidstone, England) using a multiple automated sample harvester unit (MASH II; MA Bioproducts, Walkersville, MD). Cellular uptake of thymidine was quantified in a liquid scintillation counter (LS 8000, Beckman Instruments, Irvine, CA). Results are expressed as the mean net Bq (stimulated minus control) of triplicate cultures (Hosack-Fowler et al. 1993b).
Interleukin-2 quantitation.
Splenic lymphocytes were isolated, cultured and stimulated as described above. At 48 h post Con A-addition, 100-µL aliquots of culture supernatant were harvested and stored at 80°C. In preliminary experiments, a 48 h incubation yielded maximal IL-2 secretion relative to the 96 h culture time used for proliferation measurements (data not shown). Culture supernatant was thawed, gently vortexed, and centrifuged for 1 min at 100 × g. An aliquot (50 µL) of the culture supernatant was analyzed quantitatively for IL-2 using a commercially available ELISA kit (Genzyme, Cambridge, MA). The results are expressed as the mean ± SEM (n = 5) in pg/200,000 cells from two independent diet studies.
T-lymphocyte CD4+ and CD8+ analysis.
Splenic lymphocytes were isolated as described above. The cells were resuspended in 2 mL of ACK lysis buffer (0.15 mol/L NH4Cl, 1 mmol/L KHCO3, 0.1 mmol/L Na2EDTA in ddH2O, pH 7.4) and incubated on ice for 5 min to remove red blood cells. The cells were washed once, and cell viability was determined by trypan blue exclusion. Cells (1 × 106) were incubated for 10 min on ice with 1 mL blocking solution (Hank's PBS with 10% heat-inactivated horse serum). A 2 mL aliquot of staining buffer (Hank's PBS with 10% FBS and 0.1 g/L NaN3) was used to wash the cells three times. Pelleted cells were resuspended in 300 µL of staining buffer to which 50 µL (1 µg) of either mAb CD4 Quantum Red conjugated or mAb CD8 Quantum Red conjugated (Sigma Immuno Chemicals) was added. Antibody concentrations were titrated in preliminary experiments to obtain maximal fluorescence in our cell system (data not shown). The antibody/cell mixtures were wrapped in aluminum foil on a table top shaker and incubated for 1 h on ice. The T cells were washed three times with 2 mL of staining buffer, resuspended in 1 mL staining buffer, and analyzed by FACScan (Coulter Corp., Hialeah, FL). Results are expressed as the mean ± SEM (n = 4) percentage of total splenocytes.
Diacylglycerol and ceramide quantitation.
Splenic lymphocytes were resuspended at 5 × 109 cells/L in prewarmed (37°C) complete medium to which Con A was added at a final concentration of 10 mg/L. The cells were vortexed gently and incubated in a 37°C water bath. At 2, 5, 20, 45, 60, 120 and 180 min, the cell suspension was gently vortexed, and 1-mL aliquots of cells were transferred to a 2.0-mL microcentrifuge tube. The cell aliquot for the time 0 value was obtained immediately prior to Con A addition. Lymphocyte cellular lipids were extracted, and DAG and ceramide were quantitated using the DAG kinase assay as previously described (Jolly et al. 1996).
Statistical analysis.
The data were analyzed by one-way analysis of variance at each time point using SAS (SAS 1995). Also, within each diet group, the effect of time was evaluated using one-way analysis of variance. Differences between means were tested using Duncan's multiple range test. Differences were considered significant at P < 0.05.
RESULTS
Table 1.
Effect of dietary lipid on the distribution of splenic CD4+ and CD8+ T-lymphocytes in mice1
Fig. 2.
Down-regulation of mitogen-induced murine splenocyte interleukin-2 secretion in vitro by dietary eicosapentaenoic acid and docosahexaenoic acid. Mice were fed for 10 d and splenic lymphocytes were stimulated as described in Figure 1. IL-2 in the culture supernatant was quantitated by ELISA as described in Materials and Methods. Values (n = 5 mice) represent the mean ± SEM in pg/200,000 cells from two independent diet studies. Different letters denote significant (P < 0.05) differences. SAF = safflower oil ethyl esters, AA = arachidonic acid triglyceride, EPA = eicosapentaenoic acid ethyl ester, DHA = docosahexaenoic acid ethyl ester.
[View Larger Version of this Image (30K GIF file)]
) and is produced in a multiphasic fashion in Con A-activated murine splenic lymphocytes (Jolly et al. 1996). Figure 3A shows the effects of dietary lipid on Con A-induced DAG kinetics. There was no significant difference in basal DAG mass (t = 0) between the four diet groups. Con A induced a significant (P < 0.05) increase in DAG mass at 2, 60, 120 and 180 min (33, 34.6, 29.4 and 29.2 pmol/106 cells, respectively) compared to basal levels (22.4 pmol/106 cells at t = 0) in SAF-fed mice. A slightly different kinetic pattern was observed in AA-fed mice in that Con A stimulation induced a significant (P < 0.05) increase in DAG mass at 2, 5, 20, 60, 120 and 180 min (31.5, 27.8, 32.5, 28.8, 34.5 and 35.5 pmol/106 cells, respectively) compared to basal levels (17.7 pmol/106 cells). There was no significant (P > 0.05) difference in mitogen-induced DAG mass between AA and SAF feeding except at 5 min, at which point DAG mass was significantly (P < 0.05) lower relative to SAF-fed mice. In sharp contrast, Con A-induced DAG mass was significantly (P < 0.05) suppressed at all the time points in DHA-fed mice compared to AA-fed mice. EPA feeding also resulted in a significant (P < 0.05) reduction in DAG mass at 2, 5, 20, 45, 120 and 180 min relative to AA feeding. Mitogen-induced DAG mass was significantly (P < 0.05) reduced at all time points in DHA-fed mice compared to SAF feeding, except at 5 min. Furthermore, EPA feeding significantly (P < 0.05) suppressed DAG mass at 2, 20, 45 and 180 min relative to SAF feeding. EPA and DHA-fed mice did not differ significantly (P > 0.05) from each other in Con A-induced DAG mass at any of the time points measured.
Effect of diet on splenocyte ceramide kinetics in response to Con A. Ceramide is a novel intracellular lipid second messenger that plays a positive role in the T-lymphocyte proliferative response (Chan and Ochi 1995
). Con A-activated murine splenic lymphocytes produced ceramide in a single prolonged transient peak (Jolly et al. 1996). Figure 3B illustrates the effects of dietary lipid on Con A-induced ceramide production in splenic lymphocyte cultures. Basal (t = 0) ceramide mass was not significantly (P > 0.05) different among the four diets. The AA-fed mice showed a significant increase (P < 0.05) in ceramide mass at 2 min (23.4 pmol/106 cells) compared to basal levels (11.4 pmol/106 cells) which remained significantly elevated for 180 min. A similar kinetic pattern was observed with SAF feeding in that Con A induced a significant (P < 0.05) increase in ceramide mass at 2 min (22.3 pmol/106 cells) relative to basal (15.0 pmol/106 cells), and remained significantly elevated through the end of the 180 min experiment. Ceramide mass did not significantly (P > 0.05) differ between SAF- and AA-fed mice or between EPA- and DHA-fed mice at any of the time points measured. In contrast, Con A did not induce an increase in ceramide mass in EPA- or DHA-fed mice. Both EPA and DHA feeding were associated with significant (P < 0.05) reductions in mitogen-induced ceramide mass at all the time points measured relative to AA- and SAF-fed mice.
DISCUSSION
). Furthermore, EPA and DHA were significantly incorporated into the cellular lipids of T-lymphocytes, key immune cells in propagating the DTH response (Hosack-Fowler et al. 1993b). To extend these observations, we report here the effect of dietary EPA and DHA on T-lymphocyte function in vitro. Both EPA and DHA significantly suppressed IL-2 production (Fig. 2) and the subsequent proliferative response (Fig. 1). This effect was apparently not due to major alterations in the proportions of CD4+ or CD8+ T-lymphocyte subsets since there was no significant dietary effect on the distribution of these two phenotypes in the spleen (Table 1). Therefore, the data indicate that dietary EPA and DHA affect the process of T-lymphocyte activation. This is corroborated by the observation that dietary EPA and DHA blunted mitogen-induced DAG (Fig. 3A) and ceramide (Fig. 3B) production within T-cells, strongly suggesting that lymphocyte function was altered by dietary influences on cell signalling pathways. The effect of low doses (10 g/kg) of dietary EPA and DHA on T-cell functions most likely is not due to alterations in membrane fluidity because cells can alter their membrane lipid composition to maintain a relatively constant fluidity in response to at least moderate levels of dietary lipid manipulation (Hagve 1988). In addition, the observed effects are likely the result of EPA and DHA substitution and not essential fatty acid deficiency because sufficient quantities of linoleic acid (in the form of SAF) were present in all the experimental diets.
). Furthermore, our data show that the intake of a low fat (3% of total energy intake), EPA or DHA enriched diet consumed for only 10 d can have a profound effect on T-lymphocyte proliferation. This novel demonstration of the sensitivity of lymphocyte function to even modest dietary intervention has important implications for the therapeutic application of EPA and DHA. The dietary AA effect did not significantly differ from SAF fed mice, showing that the suppressed proliferative response was due to EPA and DHA substitution, and not the reduction in linoleic acid content in the diet.
). That observation has been extended by showing that a low fat (approximately 25% of energy), fish [(n-3) fatty acid] enriched diet consumed by human subjects for 24 wk led to reduced Con A-induced T-lymphocyte proliferation as well as a suppressed DTH response in vivo (Meydani et al. 1993). However, the patterns of T-lymphocyte proliferation were different from our previously published observations (Hosack-Fowler et al. 1993b). This may be due to the overall difference in the magnitude of activation as reflected by major differences in the control (SAF) group proliferative responses in the two studies.
, Minami and Taniguchi 1995). Therefore, we examined the effect of dietary fatty acids on Con A-induced IL-2 secretion into the culture medium. Both EPA and DHA feeding reduced IL-2 secretion (Fig. 2) suggesting that the suppressed lymphoproliferation we observed is due, at least in part, to a reduction in IL-2. Fish oil feeding has previously been shown to reduce IL-2 production in humans, in association with suppressed T-lymphocyte proliferation (Endres et al. 1993, Meydani et al. 1991). Our results extend these observations by showing that both highly purified EPA and DHA can attenuate IL-2 production.
).
). We have previously shown that DAG is produced in a multiphasic fashion in Con A-stimulated murine splenocytes (Jolly et al. 1996). In this study, both EPA and DHA feeding practically abolished mitogen-induced DAG production while AA had no effect relative to the SAF-fed mice (Fig. 3A). While the multiphasic nature of DAG formation in SAF and AA-fed mice is similar to our previous observations (Jolly et al. 1996) the magnitude of the response is different. This most likely is due to the use of mice fed nonpurified diet in our initial study, rather than the semi-purified control (SAF and AA) diets employed here. There were no differences in basal DAG mass between any of the diet groups (Fig. 3A) indicating that dietary EPA and DHA modulate receptor mediated DAG production and not basal steady-state levels, ruling out a general metabolic defect in EPA and DHA enriched splenic lymphocytes. These results differ from earlier reports (Hosack-Fowler et al. 1993a and 1993b) possibly because in those studies, splenic lymphocytes were preincubated for 16 h, which can alter the T-cell proliferative response and potentially the generation of intracellular lipid second messengers (unpublished observations, Goodwin et al. 1978). In this work, freshly isolated T-cells were immediately activated, allowing for the correlation between DAG mass and T-cell proliferation. We are the first to directly demonstrate an effect of dietary EPA and DHA on activation-induced DAG production, although a previous study had suggested such an effect by showing alterations in neutrophil PI metabolism in response to fish oil feeding (Sperling et al. 1993).
). Our previous results show that Con A induces a transient prolonged increase of ceramide in murine splenocytes (Jolly et al. 1996). Furthermore, we established that ceramide is a positive effector molecule with respect to T-lymphocyte proliferation in a splenocyte culture system (Jolly et al. 1996). The present results clearly show that both dietary EPA and DHA blunt Con A-induced ceramide generation (Fig. 3B) which is positively correlated with the diet effects on lymphoproliferation (Fig. 1) and IL-2 secretion (Fig. 2). While the prolonged ceramide formation seen in SAF- and AA-fed mice is similar to our previous observations (Jolly et al. 1996) the magnitude of the response is different. This may be due to the use of mice fed nonpurified diet in our initial study and not the semi-purified diets employed here. Interestingly, IL-2 stimulation reduces ceramide mass in human T cells (Borchardt et al. 1994). This suggests that ceramide is important only at certain time points in the T-lymphocyte cell cycle, i.e., ceramide is needed for IL-2 synthesis but is no longer required or possibly is inhibitory if present during IL-2 stimulation.
) which, as would be expected, correlates with suppressed T-lymphocyte IL-2 secretion and subsequent proliferation in vitro (Figs. 1, 2). In an attempt to elucidate the mechanism(s) of action, we demonstrate that both dietary EPA and DHA suppress the time-dependent production of Con A-induced lymphocyte DAG and ceramide mass (Figs. 3A, B). Con A was chosen as the activating agent because, as is the case with in vivo responses, it perturbs multiple T-cell plasma membrane receptors. Using this novel feeding regimen, we are the first to show the modulation of DAG and ceramide mass in lymphocytes by dietary EPA and DHA in response to stimulation. This work also complements the hypothesis that DAG and ceramide play positive roles in IL-2 secretion. Additional studies are required to further elucidate the mechanisms of immunomodulation by dietary fish oil to optimize its potential beneficial effects.
FOOTNOTES
Manuscript received 24 June 1996. Initial reviews completed 21 August 1996. Revision accepted 26 September 1996.
ACKNOWLEDGMENTS
We wish to thank Susan W. Phalen and Jane Miller for their excellent technical assistance. We also thank Martek Biosciences Corporation for donating the AA triglyceride.
LITERATURE CITED
-tocopherol-fortified n-3 polyunsaturated fatty acids.
J. Nutr. Biochem.
1993;
4:153-157
-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.
J. Clin. Invest.
1993;
91:651-660
This article has been cited by other articles:
|
|
 |
|
  N. M. J. Schwerbrock, E. A. Karlsson, Q. Shi, P. A. Sheridan, and M. A. Beck Fish Oil-Fed Mice Have Impaired Resistance to Influenza Infection J. Nutr., August 1, 2009; 139(8): 1588 - 1594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. McFarland, Y.-Y. Fan, R. S. Chapkin, B. R. Weeks, and D. N. McMurray Dietary Polyunsaturated Fatty Acids Modulate Resistance to Mycobacterium tuberculosis in Guinea Pigs J. Nutr., November 1, 2008; 138(11): 2123 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, W. Li, N. Li, and J. Li {omega}-3 Fatty Acids-Supplemented Parenteral Nutrition Decreases Hyperinflammatory Response and Attenuates Systemic Disease Sequelae in Severe Acute Pancreatitis: A Randomized and Controlled Study JPEN J Parenter Enteral Nutr, May 1, 2008; 32(3): 236 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Wathes, D. R. E. Abayasekara, and R. J. Aitken Polyunsaturated Fatty Acids in Male and Female Reproduction Biol Reprod, August 1, 2007; 77(2): 190 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Petursdottir and I. Hardardottir Dietary Fish Oil Increases the Number of Splenic Macrophages Secreting TNF-{alpha} and IL-10 But Decreases the Secretion of These Cytokines by Splenic T Cells from Mice J. Nutr., March 1, 2007; 137(3): 665 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Chapkin, L. A. Davidson, L. Ly, B. R. Weeks, J. R. Lupton, and D. N. McMurray Immunomodulatory Effects of (n-3) Fatty Acids: Putative Link to Inflammation and Colon Cancer J. Nutr., January 1, 2007; 137(1): 200S - 204S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Aragona, C. Bucolo, R. Spinella, S. Giuffrida, and G. Ferreri Systemic Omega-6 Essential Fatty Acid Treatment and PGE1 Tear Content in Sjogren's Syndrome Patients Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4474 - 4479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Li, M. Wang, L. Tan, C. Wang, J. Ma, N. Li, Y. Li, G. Xu, and J. Li Docosahexaenoic acid changes lipid composition and interleukin-2 receptor signaling in membrane rafts J. Lipid Res., September 1, 2005; 46(9): 1904 - 1913. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Yun and P. Y. Lee Enhanced Fertility After Diagnostic Hysterosalpingography Using Oil-Based Contrast Agents May Be Attributable to Immunomodulation Am. J. Roentgenol., December 1, 2004; 183(6): 1725 - 1727. [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Y. Fan, L. H. Ly, R. Barhoumi, D. N. McMurray, and R. S. Chapkin Dietary Docosahexaenoic Acid Suppresses T Cell Protein Kinase C{theta} Lipid Raft Recruitment and IL-2 Production J. Immunol., November 15, 2004; 173(10): 6151 - 6160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Anderson and K. L. Fritsche Dietary Polyunsaturated Fatty Acids Modulate In Vivo, Antigen-Driven CD4+ T-Cell Proliferation in Mice J. Nutr., August 1, 2004; 134(8): 1978 - 1983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F Leitzmann, M. J Stampfer, D. S Michaud, K. Augustsson, G. C Colditz, W. C Willett, and E. L Giovannucci Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer Am. J. Clinical Nutrition, July 1, 2004; 80(1): 204 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J Field and P. D Schley Evidence for potential mechanisms for the effect of conjugated linoleic acid on tumor metabolism and immune function: lessons from n-3 fatty acids Am. J. Clinical Nutrition, June 1, 2004; 79(6): 1190S - 1198S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kew, M. D Mesa, S. Tricon, R. Buckley, A. M Minihane, and P. Yaqoob Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans Am. J. Clinical Nutrition, April 1, 2004; 79(4): 674 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kew, S. Wells, F. Thies, G. P. McNeill, P. T. Quinlan, G. T. Clark, H. Dombrowsky, A. D. Postle, and P. C. Calder The Effect of Eicosapentaenoic Acid on Rat Lymphocyte Proliferation Depends Upon Its Position in Dietary Triacylglycerols J. Nutr., December 1, 2003; 133(12): 4230 - 4238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-Y. Fan, D. N. McMurray, L. H. Ly, and R. S. Chapkin Dietary (n-3) Polyunsaturated Fatty Acids Remodel Mouse T-Cell Lipid Rafts J. Nutr., June 1, 2003; 133(6): 1913 - 1920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Y. Lee, A. Plakidas, W. H. Lee, A. Heikkinen, P. Chanmugam, G. Bray, and D. H. Hwang Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids J. Lipid Res., March 1, 2003; 44(3): 479 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Switzer, D. N. McMurray, J. S. Morris, and R. S. Chapkin (n-3) Polyunsaturated Fatty Acids Promote Activation-Induced Cell Death in Murine T Lymphocytes J. Nutr., February 1, 2003; 133(2): 496 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Pompos and K. L. Fritsche Antigen-Driven Murine CD4+ T Lymphocyte Proliferation and Interleukin-2 Production Are Diminished by Dietary (n-3) Polyunsaturated Fatty Acids J. Nutr., November 1, 2002; 132(11): 3293 - 3300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Field, I. R. Johnson, and P. D. Schley Nutrients and their role in host resistance to infection J. Leukoc. Biol., January 1, 2002; 71(1): 16 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Triboulot, A. Hichami, A. Denys, and N. A. Khan Dietary (n-3) Polyunsaturated Fatty Acids Exert Antihypertensive Effects by Modulating Calcium Signaling in T Cells of Rats J. Nutr., September 1, 2001; 131(9): 2364 - 2369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Thies, G. Nebe-von-Caron, J. R. Powell, P. Yaqoob, E. A. Newsholme, and P. C. Calder Dietary Supplementation with {{gamma}}-Linolenic Acid or Fish Oil Decreases T Lymphocyte Proliferation in Healthy Older Humans J. Nutr., July 1, 2001; 131(7): 1918 - 1927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Arrington, D. N. McMurray, K. C. Switzer, Y.-Y. Fan, and R. S. Chapkin Docosahexaenoic Acid Suppresses Function of the CD28 Costimulatory Membrane Receptor in Primary Murine and Jurkat T Cells J. Nutr., April 1, 2001; 131(4): 1147 - 1153. [Abstract] [Full Text]
|
|
|
|
|
|
F. A. Wallace, E. A. Miles, C. Evans, T. E. Stock, P. Yaqoob, and P. C. Calder Dietary fatty acids influence the production of Th1- but not Th2-type cytokines J. Leukoc. Biol., March 1, 2001; 69(3): 449 - 457. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. Weindruch, K. P. Keenan, J. M. Carney, G. Fernandes, R. J. Feuers, R. A. Floyd, J. B. Halter, J. J. Ramsey, A. Richardson, G. S. Roth, et al. Caloric Restriction Mimetics: Metabolic Interventions J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2001; 56(90001): 20 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Toft, M. Thorn, K. Ostrowski, S. Asp, K. Moller, S. Iversen, C. Hermann, S. R. Sondergaard, and B. K. Pedersen N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise J Appl Physiol, December 1, 2000; 89(6): 2401 - 2406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Pedersen and A. D. Toft Effects of exercise on lymphocytes and cytokines Br. J. Sports Med., August 1, 2000; 34(4): 246 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. O. Lim, C. A. Jolly, K. Zaman, and G. Fernandes Dietary (n-6) and (n-3) Fatty Acids and Energy Restriction Modulate Mesenteric Lymph Node Lymphocyte Function in Autoimmune-Prone (NZB NZW)F1 Mice J. Nutr., July 1, 2000; 130(7): 1657 - 1664. [Abstract] [Full Text]
|
|
|
|
|
|
C. J Field Use of T cell function to determine the effect of physiologically active food components Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1720S - 1725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Vesper, E.-M. Schmelz, M. N. Nikolova-Karakashian, D. L. Dillehay, D. V. Lynch, and A. H. Merrill Jr. Sphingolipids in Food and the Emerging Importance of Sphingolipids to Nutrition J. Nutr., July 1, 1999; 129(7): 1239 - 1250. [Abstract] [Full Text]
|
|
|
|
|
|
P. M. Byleveld, G. T. Pang, R. L. Clancy, and D. C. K. Roberts Fish Oil Feeding Delays Influenza Virus Clearance and Impairs Production of Interferon-{gamma} and Virus-Specific Immunoglobulin A in the Lungs of Mice J. Nutr., February 1, 1999; 129(2): 328 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-Y. Fan and R. S. Chapkin Importance of Dietary gamma -Linolenic Acid in Human Health and Nutrition J. Nutr., September 1, 1998; 128(9): 1411 - 1414. [Abstract] [Full Text]
|
|
|
|
|
|
S. Xi, D. Cohen, and L. H. Chen Effects of fish oil on cytokines and immune functions of mice with murine AIDS J. Lipid Res., August 1, 1998; 39(8): 1677 - 1687. [Abstract] [Full Text]
|
|
|
|
|
|
S. Bechoua, M. Dubois, G. Némoz, M. Lagarde, and A.-F. Prigent Docosahexaenoic acid lowers phosphatidate level in human activated lymphocytes despite phospholipase D activation J. Lipid Res., April 1, 1998; 39(4): 873 - 883. [Abstract] [Full Text]
|
|
|
|
|
|
L. E. Robinson and C. J. Field Dietary Long-Chain (n-3) Fatty Acids Facilitate Immune Cell Activation in Sedentary, but not Exercise-Trained Rats J. Nutr., March 1, 1998; 128(3): 498 - 504. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
