title: α-Tocopherol long-chain metabolite α-13'-COOH affects the inflammatory response of lipopolysaccharide-activated murine RAW264.7 macrophages.
abstract: METHODS
  Inflammatory response of macrophages is regulated by vitamin E forms. The long-chain metabolite α-13'-carboxychromanol (α-13'-COOH) is formed by hepatic α-tocopherol (α-TOH) catabolism and acts as a regulatory metabolite via pathways that are different from its metabolic precursor.
  
  
  RESULTS
  Using semisynthetically-derived α-13'-COOH we profiled its action on LPS-induced expression of pro- and anti-inflammatory genes using RT-qPCR and of key proteins by Western blotting. Effects on inflammatory response were assessed by measuring production of nitric oxide and prostaglandin (PG) E2 , PGD2 , and PGF2α. α-13'-COOH inhibits proinflammatory pathways in LPS-stimulated RAW264.7 macrophages more efficiently than α-TOH. Profiling inflammation-related genes showed significant blocking of interleukin (Il)1β by the metabolite and its precursor as well, while upregulation of Il6 was not impaired. However, induction of Il10, cyclooxygenase 2 (Cox2) and inducible nitric oxide synthase (iNos) by LPS and consequently the formation of nitric oxide and PG was significantly reduced by α-13'-COOH. Interestingly, α-13'-COOH acted independently from translocation of NFκB subunit p65.
  
  
  CONCLUSIONS
  Our study sheds new light on the mode of action of α-TOH on the inflammatory response in macrophages, which may be mediated in vivo at least in part by its metabolite α-13'-COOH. Our data show that α-13'-COOH is a potent anti-inflammatory molecule.
authors.affiliation: Department of Nutritional Biochemistry and Physiology, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany.|Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wallert
authors.affiliation: Department of Nutritional Biochemistry and Physiology, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany.|Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schmölz
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Krauth
authors.affiliation: Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), Friedrich Schiller University Jena, Jena, Germany.|Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.|Department of Nutrition Toxicology, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Glei
authors.affiliation: Department of Pharmaceutical Sciences, Laboratory of Nutrition and Clinical Biochemistry, University of Perugia, Perugia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Galli
authors.affiliation: Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), Friedrich Schiller University Jena, Jena, Germany.|Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Nutritional, Food and Consumer Studies, HS Fulda - University of Applied Sciences, Fulda, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Birringer
authors.affiliation: Department of Nutritional Biochemistry and Physiology, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany.|Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorkowski
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001578:Benzopyrans / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056747:Immunomodulation / Q000187:drug effects; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067996:RAW 264.7 Cells; D051996:Transcription Factor RelA / Q000378:metabolism; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C000607530:13'-(6-hydroxy-2,5,7,8,-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D005227:Fatty Acids; C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D016753:Interleukin-10; D009569:Nitric Oxide; D015237:Dinoprost; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D024502:alpha-Tocopherol; D015232:Dinoprostone; D015230:Prostaglandin D2
keywords: Inflammation; Inflammatory response; Macrophage activation; Macrophages; α-13’-COOH; α-Tocopherol