Formononetin, a phyto-oestrogen, and its metabolites up-regulate interleukin-4 production in activated T cells via increased AP-1 DNA binding activity.
Phyto-oestrogens are polyphenolic non-steroidal plant compounds with oestrogen-like biological activity. Phyto-oestrogens have many biological effects including oestrogen agonist/antagonist properties. However, the effect of phyto-oestrogens on allergic responses remains unclear. In this study we investigated whether formononetin, a phyto-oestrogen, and its metabolites, daidzein and equol, affect production of interleukin-4 (IL-4), a pro-inflammatory cytokine closely associated with allergic immune response, in primary CD4+ T cells and EL4 T lymphoma cells. Formononetin, daidzein and equol significantly enhanced IL-4 production from both CD4+ T cells and EL4 cells in a dose-dependent manner. Formononetin, daidzein and equol also enhanced IL-4 gene promoter activity in EL4 cells transiently transfected with IL-4 gene promoter constructs, but this effect was impaired in EL4 cells transfected with an IL-4 promoter construct deleted of P4 site carrying nuclear factor of activated T cells (NF-AT) and activator protein-1 (AP-1) binding sites. In addition, formononetin, daidzein and equol increased AP-1 DNA binding activities while did not affect NF-AT DNA binding activities. The enhancing effects on IL-4 production and AP-1 DNA binding activities were abrogated by specific inhibitors for phosphatidylinositol-3-kinase (PI3K), protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), indicating that formononetin, daidzein and equol might enhance IL-4 production by increased activation of AP-1 through the PI3-K/PKC/p38 MAPK signalling pathway. These results suggest that phyto-oestrogens and some of their metabolites may increase allergic responses via the enhancement of IL-4 production in T cells.
Park
Jin
J
School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Kim
Seung H
SH
Cho
Daeho
D
Kim
Tae S
TS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D060754:Equol; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis*; D007529:Isoflavones / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D048789:Phytoestrogens / Q000494:pharmacology*; D011493:Protein Kinase C / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
C007610:4',7-dihydroxy-3,4-dihydroisoflavone; D004268:DNA-Binding Proteins; D007529:Isoflavones; D048789:Phytoestrogens; D018808:Transcription Factor AP-1; D015847:Interleukin-4; C007768:formononetin; D060754:Equol; C004742:daidzein; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate