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- Title
Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase.
- Authors
Pein, Helmut; Ville, Alexia; Pace, Simona; Temml, Veronika; Garscha, Ulrike; Raasch, Martin; Alsabil, Khaled; Viault, Guillaume; Dinh, Chau-Phi; Guilet, David; Troisi, Fabiana; Neukirch, Konstantin; König, Stefanie; Bilancia, Rosella; Waltenberger, Birgit; Stuppner, Hermann; Wallert, Maria; Lorkowski, Stefan; Weinigel, Christina; Rummler, Silke
- Abstract
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-06158-5