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Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ
| Title: | Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ |
| Authors: | Kojima, Hiroyuki Browse this author | | Muromoto, Ryuta Browse this author →KAKEN DB | | Takahashi, Miki Browse this author | | Takeuchi, Shinji Browse this author | | Takeda, Yukimasa Browse this author | | Jetten, Anton M. Browse this author | | Matsuda, Tadashi Browse this author →KAKEN DB |
| Keywords: | Fungicide | | Interleukin 17 | | Mouse | | Reporter gene assay | | Retinoic acid receptor-related orphan receptor |
| Issue Date: | 15-Mar-2012 |
| Publisher: | Elsevier |
| Journal Title: | Toxicology and Applied Pharmacology |
| Volume: | 259 |
| Issue: | 3 |
| Start Page: | 338 |
| End Page: | 345 |
| Publisher DOI: | 10.1016/j.taap.2012.01.011 |
| Abstract: | The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, trifiumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10^[-6] M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/49116 |
| 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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