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Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase
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Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase
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Journal Article
Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase
2018
Overview
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-((2
R
)-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.
Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 101/62
/ 13
/ 13/95
/ 14
/ 38/70
/ 64/60
/ 82/16
/ 96/98
/ Adult
/ Aged
/ Animals
/ Arachidonate 5-Lipoxygenase - chemistry
/ Arachidonate 5-Lipoxygenase - metabolism
/ Asthma
/ Bronchial Hyperreactivity - pathology
/ Cell Survival - drug effects
/ Exudates
/ Humanities and Social Sciences
/ Humans
/ Lipoxygenase Inhibitors - pharmacology
/ Liver
/ Mice
/ Recombinant Proteins - metabolism
/ Science
