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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)
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Submitter: 松田 正
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