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

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概要

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• 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.

• 2012-03-15

著者

• Kojima Hiroyuki

  Hokkaido Institute of Public Health

• Takeuchi Shinji

  Hokkaido Institute of Public Health

関連論文

• Endocrine-disrupting Potential of Pesticides via Nuclear Receptors and Aryl Hydrocarbon Receptor
• Comparative Study on the Nuclear Hormone Receptor Activity of Various Phytochemicals and Their Metabolites by Reporter Gene Assays Using Chinese Hamster Ovary Cells(Molecular and Cell Biology)
• Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

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