Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

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

doi:10.1016/j.tox.2015.01.007

Cited by 24 publications

(23 citation statements)

References 41 publications

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“…Our previous study [7] and its confirmatory experiment ( Figure 1E) showed that biochanin A enhanced Il17a expression in the PMA/ionomycin-stimulated EL4 murine tumor cell line, which constitutively expresses RORγ [13]. Figures S1A and S1B), indicating that the biochanin A-induced activation of Il17-promoter can be reconstituted in non-lymphoid HeLa cells.…”

Section: Knockdown Of Rorγ or Stat3 Cancels Biochanin A-induced Enhansupporting

confidence: 51%

“…Immunoprecipitation and immunoblotting assays in our previous study [7] revealed that biochanin A enhanced the interaction between RORγt and NCOA1. This finding suggests that isoflavones enhance IL-17 gene expression by stabilizing the interactions between RORα/γ and NCOA1.…”

Section: Introductionmentioning

confidence: 81%

“…NCOA1 is a transcriptional coactivator that has been reported to interact with both RORγ [10] and phosphorylated STAT3 [17] ( Figure 4A). Previously we demonstrated that NCOA1 interacts with wild type RORγ but not with the ∆AF2 mutant in a biochanin A-stimulation dependent manner [7]. We examined the role of biochanin A-induced phosphorylation of STAT3 for the complex formation between RORγt and NCOA1.…”

Section: Biochanin A-activated Stat3 Mediates Coactivator Binding To mentioning

confidence: 98%

“…We recently identified various azole pesticides, including imibenconazole, as suppressors of IL-17 gene expression [6]. Additionally, we found that four isoflavones (daidzein, genistein, formononetin and biochanin A) enhance RORα-and RORγ-mediated transcriptional activity in CHO and Jurkat cell-based reporter assays [7]. Similar to other members of the nuclear receptor family, RORs interact with coactivators or corepressors to 6 positively or negatively regulate gene transcription [8].…”

Section: Introductionmentioning

confidence: 98%

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Biochanin A enhances RORγ activity through STAT3-mediated recruitment of NCOA1

Takahashi

Muromoto

Kojima

et al. 2017

Biochemical and Biophysical Research Communications

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Interleukin (IL)-17-producing T cells play important roles in autoimmunity, chronic inflammation and host protection against extracellular bacteria and fungi. The retinoic acid receptor-related orphan receptors (ROR) α and γ are key regulators of the IL-17-producing phenotype. We previously showed that the isoflavone biochanin A enhanced ROR-mediated transcriptional activity. Here, we investigated the possible mechanisms underlying this ROR activation. Biochanin A-treated murine thymoma EL4 and primary splenocytes demonstrated enhanced induction of IL-17. Biochanin A also induced tyrosine-phosphorylation of signal transducer and activator of transcription 3 (STAT3) in these cells. Stable knockdown of either RORγ or STAT3 in EL4 cells canceled biochanin A-induced upregulation of IL-17 expression. Importantly, biochanin A enhanced complex formation between RORγ and STAT3 or nuclear-receptor coactivator 1 (NCOA1). Furthermore, the biochanin A-induced RORγ-NCOA1 complex was disrupted by a dominant negative mutant of STAT3 or by the STAT3 specific inhibitor Stattic. These results suggest that biochanin A activates RORγ-dependent IL-17 transcription through the enhancement of STAT3 phosphorylation and STAT3-mediated recruitment of NCOA1 to RORγ.

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Section: Knockdown Of Rorγ or Stat3 Cancels Biochanin A-induced Enhansupporting

confidence: 51%

Section: Introductionmentioning

confidence: 81%

Section: Biochanin A-activated Stat3 Mediates Coactivator Binding To mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Biochanin A enhances RORγ activity through STAT3-mediated recruitment of NCOA1

Takahashi

Muromoto

Kojima

et al. 2017

Biochemical and Biophysical Research Communications

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“…This was surprising, as to the best of our knowledge a role for this gene within BM-MSC and/or immune biology has not been previously reported. However, another retinoid-related gene, Retinoic Acid Receptor-Related Orphan Receptor alpha ( RORA ), for which a role in pro-inflammatory cytokine regulation is described24 also had a high degree (2,609) of connectivity and was present within the clique (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells

Anderson

Kalimutho

Harten

et al. 2017

Sci Rep

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In breast cancer metastasis, the dynamic continuum involving pro-and anti-inflammatory regulators can become compromised. Over 600 genes have been implicated in metastasis to bone, lung or brain but how these genes might contribute to perturbation of immune function is poorly understood. To gain insight, we adopted a gene co-expression network approach that draws on the functional parallels between naturally occurring bone marrow-derived mesenchymal stem cells (BM-MSCs) and cancer stem cells (CSCs). Our network analyses indicate a key role for metastasis suppressor RARRES3, including potential to regulate the immunoproteasome (IP), a specialized proteasome induced under inflammatory conditions. Knockdown of RARRES3 in near-normal mammary epithelial and breast cancer cell lines increases overall transcript and protein levels of the IP subunits, but not of their constitutively expressed counterparts. RARRES3 mRNA expression is controlled by interferon regulatory factor IRF1, an inducer of the IP, and is sensitive to depletion of the retinoid-related receptor RORA that regulates various physiological processes including immunity through modulation of gene expression. Collectively, these findings identify a novel regulatory role for RARRES3 as an endogenous inhibitor of IP expression, and contribute to our evolving understanding of potential pathways underlying breast cancer driven immune modulation.

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Controversy on health-based guidance values for bisphenol A—the need of criteria for studies that serve as a basis for risk assessment

Leist,

Buettner,

Diel

et al. 2024

Arch Toxicol

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Since 2006, the responsible regulatory bodies have proposed five health-based guidance values (HBGV) for bisphenol A (BPA) that differ by a factor of 250,000. This range of HBGVs covers a considerable part of the range from highly toxic to relatively non-toxic substances. As such heterogeneity of regulatory opinions is a challenge not only for scientific risk assessment but also for all stakeholders, the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) analyzed the reasons for the current discrepancy and used this example to suggest improvements for the process of HBGV recommendations. A key aspect for deriving a HBGV is the selection of appropriate studies that allow the identification of a point of departure (PoD) for risk assessment. In the case of BPA, the HBGV derived in the 2023 EFSA assessment was based on a study that reported an increase of Th17 cells in mice with a benchmark dose lower bound (BMDL40) of 0.53 µg/kg bw/day. However, this study does not comply with several criteria that are important for scientific risk assessment: (1) the selected end-point, Th17 cell frequency in the spleen of mice, is insufficiently understood with respect to health outcomes. (2) It is unclear, by which mechanism BPA may cause an increase in Th17 cell frequency. (3) It is unknown, if an increase of Th17 cell frequency in rodents is comparably observed in humans. (4) Toxicokinetics were not addressed. (5) Neither the raw data nor the experimental protocols are available. A further particularly important criterion (6) is independent data confirmation which is not available in the present case. Previous studies using other readouts did not observe immune-related adverse effects such as inflammation, even at doses orders of magnitude higher than in the Th17 cell-based study. The SKLM not only provides here key criteria for the use of such studies, but also suggests that the use of such a “checklist” requires a careful and comprehensive scientific judgement of each item. It is concluded that the Th17 cell-based study data do not represent an adequate basis for risk assessment of BPA.

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Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

Cited by 24 publications

References 41 publications

Biochanin A enhances RORγ activity through STAT3-mediated recruitment of NCOA1

Biochanin A enhances RORγ activity through STAT3-mediated recruitment of NCOA1

The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells

Controversy on health-based guidance values for bisphenol A—the need of criteria for studies that serve as a basis for risk assessment

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