title: Comparative effects of n-3, n-6 and n-9 unsaturated fatty acid-rich diet consumption on lupus nephritis, autoantibody production and CD4+ T cell-related gene responses in the autoimmune NZBWF1 mouse.
abstract: Mortality from systemic lupus erythematosus (SLE), a prototypical autoimmune disease, correlates with the onset and severity of kidney glomerulonephritis. There are both preclinical and clinical evidence that SLE patients may benefit from consumption of n-3 polyunsaturated fatty acids (PUFA) found in fish oil, but the mechanisms remain unclear. Here we employed the NZBWF1 SLE mouse model to compare the effects of dietary lipids on the onset and severity of autoimmune glomerulonephritis after consuming: 1) n-3 PUFA-rich diet containing docosahexaenoic acid-enriched fish oil (DFO), 2) n-6 PUFA-rich Western-type diet containing corn oil (CRN) or 3) n-9 monounsaturated fatty acid (MUFA)-rich Mediterranean-type diet containing high oleic safflower oil (HOS). Elevated plasma autoantibodies, proteinuria and glomerulonephritis were evident in mice fed either the n-6 PUFA or n-9 MUFA diets, however, all three endpoints were markedly attenuated in mice that consumed the n-3 PUFA diet until 34 wk of age. A focused PCR array was used to relate these findings to the expression of 84 genes associated with CD4+ T cell function in the spleen and kidney both prior to and after the onset of the autoimmune nephritis. n-3 PUFA suppression of autoimmunity in NZBWF1 mice was found to co-occur with a generalized downregulation of CD4+ T cell-related genes in kidney and/or spleen at wk 34. These genes were associated with the inflammatory response, antigen presentation, T cell activation, B cell activation/differentiation and leukocyte recruitment. Quantitative RT-PCR of representative affected genes confirmed that n-3 PUFA consumption was associated with reduced expression of CD80, CTLA-4, IL-10, IL-18, CCL-5, CXCR3, IL-6, TNF-α and osteopontin mRNAs in kidney and/or spleens as compared to mice fed n-6 PUFA or n-9 MUFA diets. Remarkably, many of the genes identified in this study are currently under consideration as biomarkers and/or biotherapeutic targets for SLE and other autoimmune diseases.
authors.affiliation: Department of Food Science and Human Nutrition, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America; Center for Integrative Toxicology, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America; Department of Microbiology and Molecular Genetics, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
authors.affiliation: Department of Food Science and Human Nutrition, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America; Center for Integrative Toxicology, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Vines
authors.affiliation: Department of Food Science and Human Nutrition, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America; Center for Integrative Toxicology, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Bates
authors.affiliation: Center for Integrative Toxicology, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America; Department of Microbiology and Molecular Genetics, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: He
authors.affiliation: Division of Anatomic Pathology, Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Langohr
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D019301:Oleic Acid / Q000494:pharmacology*; D011507:Proteinuria / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001323:Autoantibodies; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; D007074:Immunoglobulin G; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019301:Oleic Acid