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. 2025 Mar;80(3):896-900.
doi: 10.1111/all.16410. Epub 2024 Dec 11.

Kaempferol Exerts Anti-Inflammatory Effects by Accelerating Treg Development via Aryl Hydrocarbon Receptor-Mediated and PU.1/IRF4-Dependent Transactivation of the Aldh1a2/Raldh2 Gene in Dendritic Cells

Miki Takahashi  1 , Kazuki Nagata  1 , Yumi Watanuki  1 , Masaki Yamaguchi  1 , Kenta Ishii  1 , Tomohiro Harada  1 , Natsuki Minamikawa  1 , Mayuka Katagiri  1 , Weiting Zhao  1 , Naoto Ito  1 , Takuya Yashiro  1 , Chiharu Nishiyama  1
Affiliations

Kaempferol Exerts Anti-Inflammatory Effects by Accelerating Treg Development via Aryl Hydrocarbon Receptor-Mediated and PU.1/IRF4-Dependent Transactivation of the Aldh1a2/Raldh2 Gene in Dendritic Cells

Miki Takahashi et al. Allergy. 2025 Mar.
No abstract available

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Kaempferol upregulates the gene expression and function of Raldh2 in DCs by antagonizing AhR. (A, B) The enzyme activity of Raldh2 in kaempferol‐treated (KAE) or non‐treated (−) BMDCs (A) and CD11c+/MHC IIhigh migDCs from MLNs (B). BMDCs and MLN cells were treated with 50 μM kaempferol for 48 h (A) and 24 h (B), respectively. (C) The frequency of Tregs. Naïve CD4+ T cells were co‐cultured with OVA peptide‐pulsed BMDCs in the presence (KAE) or absence (−) of 50 μM kaempferol for 72 h. (D) The mRNA levels of Aldh1a2 and Ahr in Ahr siRNA‐transfected BMDCs. AhR siRNA‐transfected BMDCs were cultured in the presence (KAE) or absence (−) of 50 μM kaempferol for 48 h. Cells were then harvested to assess the mRNA expression of Aldh1a2 (D left) and Ahr (D right). (E) AhR protein levels in kaempferol‐treated and/or Ahr siRNA‐transfected BMDCs. Treatment of BMDCs with siRNA and/or kaempferol was performed as that in Figure 1D. (F, G) Aldh1a2 mRNA levels (left) and Raldh2 activity (right) in BMDCs treated with an agonist (F) and an antagonist (G) of AhR. BMDCs were cultured in the presence of 100 nM TCDD for 24 h (F) and 10 μM CH‐223191 or 50 μM kaempferol (KAE) for 48 h (G). (H) The mRNA levels and activity of RALDH2 in BMDCs with the knockdown of Ido. BMDCs transfected with Ido1 and Ido2 siRNA were cultured in the presence of 50 μM kynurenine for 48 h. Data represent the mean ± SEM of six (A), five (B, H), or three (C, D, F, G) independent experiments,. Two‐tailed unpaired t‐test (A, B, C, F), Tukey's multiple comparison test (D, H), and Dunnett's multiple comparison test (G) were used for statistical analyses. *p < 0.05; **p < 0.01; n.s., not significant. KAE, Kaempferol.
FIGURE 2
FIGURE 2
Effects of the kaempferol treatment on transcription factors PU.1 and IRF4 in DCs, and on RALDH2‐related immune regulation in vivo. (A, B) The mRNA (A) and protein (B) levels of PU.1 and IRF4 in BMDCs. BMDCs were cultured in the presence (KAE) or absence (−) of 50 μM kaempferol for 8–48 h. Data of three independent experiments were quantified by calculating the band intensity, and shown as ratio to that of control (kaempferol‐non‐treated) BMDCs (Figure S3A). (C) Genomic DNA levels in BMDCs immunoprecipitated by ChIP assays using anti‐PU.1 Ab were assessed by qPCR targeting the enhancer region of the Aldh1a2 gene. BMDCs were incubated in the presence (KAE) or absence (−) of 50 μM kaempferol for approximately 24 h. ChIP‐seq profiles showing the binding of PU.1 in cDCs sorted from Flt3L‐induced BMDCs (https://chip‐atlas.org/view?id=SRX4909225) and IRF4 in GM‐CSF‐induced BMDCs (https://chip‐atlas.org/view?id=SRX185714) were obtained by using ChIP‐Atlas. (D) Aldh1a2 mRNA levels in siRNA‐transfected BMDCs. BMDCs transfected with Spi1 or Irf4 siRNA were cultured in the presence (KAE) or absence (−) of 50 μM kaempferol for 48 h. (E) Left: Western blot profiles showing protein levels of PU.1 and IRF4 in Ahr siRNA‐transfected BMDCs. Ahr siRNA‐ or control siRNA‐transfected BMDCs were cultured in the presence (KAE) or absence (−) of kaempferol for 24 h. Right: Data of three to five independent experiments were quantified by calculating the band intensity, and shown as the ratio of (PU.1 or IRF4)/(β‐actin) versus those seen in control siRNA‐transfected BMDCs without kaempferol treatment. (F) RALDH2 activity of CD11c+/MHC IIhigh migDCs in MLNs. CH‐223191 (1 mg/kg) was intraperitoneally (i.p.) administered 24 h before the analysis. (G) The frequency of Fopx3+/CD4+ cells in the Peyer's patches isolated from BMDC‐injected mice. BMDCs were pre‐incubated with (KAE) or without (−) 50 μM kaempferol for 48 h and 2.0 × 106 cells were i.p. administered to each mouse 4 days before the analysis. (H) The OVA‐induced food allergy model. A scheme of the experiment (Figure S4A). The decrease in body temperature (left), diarrhea scores (center), and the number of stools (right) of food allergy model mice after the OVA challenge (on Day 36) were evaluated. Data represent the mean ± SEM. The two‐tailed unpaired t‐test (A, F, G, H) and Tukey's multiple comparison test (C, D, E) were used for statistical analyses. *p < 0.05; **p < 0.01; # p < 0.05 (determined by t‐test in E); n.s., not significant. KAE, kaempferol.
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