title: The delta 6 desaturase knock out mouse reveals that immunomodulatory effects of essential n-6 and n-3 polyunsaturated fatty acids are both independent of and dependent upon conversion.
abstract: Typically fatty acids (FA) exert differential immunomodulatory effects with n-3 [α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and n-6 [linoleic acid (LA) and arachidonic acid (AA)] exerting anti- and pro-inflammatory effects, respectively. This over-simplified interpretation is confounded by a failure to account for conversion of the parent FA (LA and ALA) to longer-chain bioactive products (AA and EPA/DHA, respectively), thereby precluding discernment of the immunomodulatory potential of specific FA. Therefore, we utilized the Δ6-desaturase model, wherein knockout mice (D6KO) lack the Fads2 gene encoding for the rate-limiting enzyme that initiates FA metabolism, thereby providing a model to determine specific FA immunomodulatory effects. Wild-type (WT) and D6KO mice were fed one of four isocaloric diets differing in FA source (9weeks): corn oil (LA-enriched), arachidonic acid single cell oil (AA-enriched), flaxseed oil (ALA-enriched) or menhaden fish oil (EPA/DHA-enriched). Splenic mononuclear cell cytokine production in response to lipopolysaccharide (LPS), T-cell receptor (TCR) and anti-CD40 stimulation was determined. Following LPS stimulation, AA was more bioactive compared to LA, by increasing inflammatory cytokine production of IL-6 (1.2-fold) and TNFα (1.3-fold). Further, LPS-stimulated IFNγ production in LA-fed D6KO mice was reduced 5-fold compared to LA-fed WT mice, indicating that conversion of LA to AA was necessary for cytokine production. Conversely, ALA exerted an independent immunomodulatory effect from EPA/DHA and all n-3 FA increased LPS-stimulated IL-10 production versus LA and AA. These data definitively identify specific immunomodulatory effects of individual FA and challenge the simplified view of the immunomodulatory effects of n-3 and n-6 FA.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1; Guelph Food Research Centre, Agriculture Agri-Food Canada, Guelph, ON, Canada, N1G 5C9.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Monk
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Liddle
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Daniel J A
authors.initials: DJ
authors.lastname: Cohen
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Denis H
authors.initials: DH
authors.lastname: Tsang
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Hillyer
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Salma A
authors.initials: SA
authors.lastname: Abdelmagid
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA, 61801.
authors.forename: Manabu T
authors.initials: MT
authors.lastname: Nakamura
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1; Guelph Food Research Centre, Agriculture Agri-Food Canada, Guelph, ON, Canada, N1G 5C9.
authors.forename: Krista A
authors.initials: KA
authors.lastname: Power
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1. Electronic address: davidma@uoguelph.ca.
authors.forename: David W L
authors.initials: DW
authors.lastname: Ma
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1. Electronic address: lrobinso@uoguelph.ca.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D019587:Dietary Supplements; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D056747:Immunomodulation; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D008070:Lipopolysaccharides; C482199:lipopolysaccharide, E coli O55-B5; D044943:Fatty Acid Desaturases; C000616952:delta-6 desaturase, mouse
keywords: Cytokines; Fatty acid desaturase 2; Fatty acid metabolism; Inflammation; Polyunsaturated fatty acid