Research CommunicationsEffects of dietary ω3 and ω6 lipids and vitamin E on proliferative response, lymphoid cell subsets, production of cytokines by spleen cells, and splenic protein levels for cytokines and oncogenes in MRL/MpJ-lpr/lpr mice1
Introduction
Defective regulation of inflammatory responses and disordered immune mechanisms are central to the pathologic processes encountered in certain autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). RA is an autoimmune disease characterized by progressive joint destruction and immobility. Alterations in proliferative response to lectins,1 abnormal levels of serum anti-DNA antibodies,2 imbalances in pro- and anti-inflammatory cytokines,3 and increases in the expression of certain proinflammatory cytokines and oncogenes4 have been observed in RA and SLE. Various cytokines and chemokines have been implicated as important mediators of inflammation and joint destruction in RA and other inflammatory processes and prevention of cartilage erosion would be of great therapeutic benefit to patients.5 Because several autoimmune diseases are associated with overproduction of cytokines that activate inflammatory cells or responses, downregulating or blocking these proinflammatory cytokines and mediators or supplementing anti-inflammatory cytokines may have potential in delaying the disease.
There are two substrains of mice—MRL/lpr and MRL/++ mice—that offer a unique controlled model for investigating dietary and drug effects on autoimmune disease.6, 7 MRL/lpr mice spontaneously develop massive lymphadenopathy with hypergammaglobulinemia, autoantibodies, high levels of acute phase proteins, abnormal lymphoid cell subsets, expression of oncogenes in lymphoid tissues, arthritis, and immune complex glomerulonephritis compared with congenic MRL/++ mice.8 These characteristics are linked closely with the regulatory imbalance of T cells and B cells that display an exceptional constellation of altered membrane markers.9, 10 Until recently, the function of the lpr gene had been obscure, but the identification of lpr as the Fas gene, the product of which mediates a pathway for apoptosis, offers new insight into the mechanism of autoimmunity.11
The treatment of autoimmune diseases with nutrition interventions has gained attention in recent years. Nutritional interventions have been accepted as having major therapeutic potential.12, 13 Significant beneficial effects of dietary supplementation with ω3 fatty acids in autoimmune-prone mice14 and in patients with RA15 have been reported. Clinical trials using ω3 lipids containing fish oil (FO) on RA patients ameliorated clinical symptoms. RA patients who were taking FO supplements could eventually reduce the dosage of nonsteroidal anti-inflammatory drugs or even discontinue the use of medication.16 Incorporation of ω3 fatty acids into tissues may modify inflammatory and immune reactions and have a potential therapeutic value for inflammatory diseases.17 Nutritional intervention with marine lipids containing long chain ω3 fatty acids [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] have been reported to significantly increase the life span and delay the onset of autoimmune disease in autoimmune-prone mice.18
The present study was planned to examine some of the mechanisms of action of ω3 lipids and the role of vitamin E on autoimmune disease in a mouse model for RA. The major goal of this study was to investigate the immunologic mechanisms through which ω3 dietary lipids and vitamin E provide protection against autoimmune disease in MRL/lpr mice. We have investigated the effects of feeding ω3 lipids in the presence of low and high levels of vitamin E on the proliferative response of spleen cells, lymphoid cell subsets, pro- and anti-inflammatory cytokine levels, and protein levels of specific cytokines and oncogenes in MRL/lpr mice.
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Experimental animals and diets
Weanling female MRL/lpr and MRL/++ mice (10 per group) purchased from Jackson Laboratories (Bar Harbor, ME USA) were fed nutritionally-adequate semipurified diets containing 10% (w/w) corn oil (CO; ICN, Irvine, CA USA) or 10% odor-free menhaden FO (U.S. Department of Commerce, National Marine Fisheries Service, Charleston, NC USA) with low (75 IU/kg diet; LE) and high levels (500 IU/kg diet; HE) of vitamin E. Both dietary oils had equal levels of antioxidant supplements, 1.3 g/kg oil of
Results
The effects of feeding CO and FO based diets (at 10% level) containing low or high levels of vitamin E for 4.5 months to MRL/lpr and MRL/++ mice on the body weights, production of cytokines, and lipid mediators by lectin-stimulated spleen cells, lymphoid cell subsets, and Western blot analyses of spleens for oncogenes (c-myc, c-ras), interleukin (IL)-2, and transforming growth factor (TGF)-β are presented in this section.
Discussion
The present study was conducted to examine the mechanism of action of ω3 lipids and antioxidants on autoimmune disease. Results from this study indicated that both FO and high levels of vitamin E delayed the visible appearance of lymph nodes in the MRL/lpr mice. The MRL/lpr mice have a very different cytokine profile, oncogene levels, lymphoid cell subsets, and inflammatory mediators, and several of these factors may contribute to the disease. Strain, oil, and vitamin E level had significant
Acknowledgements
This research was funded by National Institute of Arthritis and Musculoskeletal and Skin Disorders grant IR15AR/AI43517. The authors wish to thank the U.S. Department of Commerce, National Marines and Fisheries Services (Charleston, NC USA) for the generous gift of antioxidants and fish oil. Wei-chia Chu was recipient of Mark Diamond Research Funds for graduate research. The authors wish to acknowledge Drs. Dean Troyer and G. Fernandes, University of Texas Health Science Center, San Antonio,
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This research was funded by National Institute of Arthritis and Musculoskeletal and Skin Disorders grant IR15AR/AI43517.