Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

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

Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

Kojima, Hiroyuki; Muromoto, Ryuta; Takahashi, Miki et al.

Toxicology and Applied Pharmacology, 2012, 259(3), 338-345

Permalink : https://hdl.handle.net/2115/49116

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アクセス権	open access
URI	https://hdl.handle.net/2115/49116
タイトル	Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ
著者	Kojima, Hiroyuki ; Muromoto, Ryuta ; Takahashi, Miki ; Takeuchi, Shinji ; Takeda, Yukimasa ; Jetten, Anton M. ; Matsuda, Tadashi
著者名 Kojima, Hiroyuki
e-Rad_Researcher 30455597 著者名 Muromoto, Ryuta
著者名 Takahashi, Miki
著者名 Takeuchi, Shinji
著者名 Takeda, Yukimasa
著者名 Jetten, Anton M.
e-Rad_Researcher 20212219 著者名 Matsuda, Tadashi
言語	英語
キーワード	Fungicide
	Interleukin 17
	Mouse
	Reporter gene assay
	Retinoic acid receptor-related orphan receptor
発行日	2012-03-15
出版者	Elsevier
収録物名	Toxicology and Applied Pharmacology
巻(号)	259(3)
ページ	338-345
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
PISSN	0041-008X
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.taap.2012.01.011