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Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors alpha and gamma

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Title: Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors alpha and gamma
Authors: Kojima, Hiroyuki Browse this author →KAKEN DB
Takeda, Yukimasa Browse this author
Muromoto, Ryuta Browse this author →KAKEN DB
Takahashi, Miki Browse this author
Hirao, Toru Browse this author
Takeuchi, Shinji Browse this author →KAKEN DB
Jetten, Anton M. Browse this author
Matsuda, Tadashi Browse this author →KAKEN DB
Keywords: Interleukin 17
Isoflavone
Luciferase assay
Retinoic acid receptor-related orphan receptor
Th17
Issue Date: 2-Mar-2015
Publisher: Elsevier
Journal Title: Toxicology
Volume: 329
Start Page: 32
End Page: 39
Publisher DOI: 10.1016/j.tox.2015.01.007
Abstract: The retinoic acid receptor-related orphan receptors a and gamma (ROR alpha and ROR gamma), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. In this study, we investigated the effects of isoflavones on ROR alpha/gamma, activity and the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In doxycycline-inducible CHO stable cell lines, we found that four isoflavones, biochanin A (BA), genistein, formononetin, and daidzein, enhanced ROR alpha- or ROR gamma-mediated transcriptional activity in a dose-dependent manner. In an activation assay of the Il17a promoter using Jurkat cells, these compounds enhanced the ROR alpha- or ROR gamma-mediated activation of the Il17a promoter at concentrations of 1 x 10(-6) M to 1 x 10(-5) M. In mammalian two-hybrid assays, the four isoflavones enhanced the interaction between the RORa- or ROR gamma-ligand binding domain and the co-activator LXXLL peptide in a dose-dependent manner. In addition, these isoflavones potently enhanced Il17a mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin, but showed slight enhancement of Il17a gene expression in ROR alpha/gamma-knockdown EL4 cells. Immunoprecipitation and immunoblotting assays also revealed that BA enhanced the interaction between ROR-gamma t and SRC-1, which is a co-activator for nuclear receptors. Taken together, these results suggest that the isoflavones have the ability to enhance IL-17 gene expression by stabilizing the interactions between ROR alpha/gamma, and co-activators. This also provides the first evidence that dietary chemicals can enhance IL-17 gene expression in immune cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
Rights: ©2015, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
http://creativecommons.org/licenses/by-nc-nd/4.0/
Type: article (author version)
URI: http://hdl.handle.net/2115/60743
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 松田 正

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