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

Kojima, Hiroyuki; Takeda, Yukimasa; Muromoto, Ryuta; Takahashi, Miki; Hirao, Toru; Takeuchi, Shinji; Jetten, Anton M.; Matsuda, Tadashi

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

Kojima, Hiroyuki; Takeda, Yukimasa; Muromoto, Ryuta et al.

Toxicology, 2015, 329, 32-39

Permalink : https://hdl.handle.net/2115/60743

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アクセス権	open access
URI	https://hdl.handle.net/2115/60743
タイトル	Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors alpha and gamma
著者	Kojima, Hiroyuki ; Takeda, Yukimasa ; Muromoto, Ryuta ; Takahashi, Miki ; Hirao, Toru ; Takeuchi, Shinji ; Jetten, Anton M. ; Matsuda, Tadashi
e-Rad_Researcher 10414286 著者名 Kojima, Hiroyuki
著者名 Takeda, Yukimasa
e-Rad_Researcher 30455597 著者名 Muromoto, Ryuta
著者名 Takahashi, Miki
著者名 Hirao, Toru
e-Rad_Researcher 20414287 著者名 Takeuchi, Shinji
著者名 Jetten, Anton M.
e-Rad_Researcher 20212219 著者名 Matsuda, Tadashi
言語	英語
キーワード	Interleukin 17
	Isoflavone
	Luciferase assay
	Retinoic acid receptor-related orphan receptor
	Th17
発行日	2015-03-02
出版者	Elsevier
収録物名	Toxicology
巻(号)	329
ページ	32-39
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
権利情報	©2015, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
PISSN	0300-483X
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.tox.2015.01.007