Abstract
Filaggrin (FLG) mutation is a well-confirmed genetic aberration in atopic dermatitis (AD). Genome-wide association studies on AD have revealed other susceptibility genes, for example, Ovo-like 1 (OVOL1). Nonetheless, the relation between FLG and OVOL1 is unclear. Because aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor), plays a role in FLG expression in keratinocytes, we hypothesized that AHR regulates FLG expression via OVOL1. To demonstrate this mechanism, we analyzed FLG expression in OVOL1-overexpressing or OVOL1-knockdown normal human epidermal keratinocytes (NHEKs). Furthermore, we tested whether AHR activation by 6-formylindolo(3,2-b)carbazole (FICZ), an endogenous AHR ligand, or Glyteer, clinically used soybean tar, upregulates FLG and OVOL1 expression in NHEKs. We found that (1) OVOL1 regulates FLG expression; (2) AHR activation upregulates OVOL1; and (3) AHR activation upregulates FLG via OVOL1. Moreover, nuclear translocation of OVOL1 was less pronounced in AD skin compared with normal skin. IL-4-treated NHEKs, an in vitro AD skin model, also showed inhibition of the OVOL1 nuclear translocation, which was restored by FICZ and Glyteer. Thus, targeting the AHR-OVOL1-FLG axis may provide new therapeutics for AD.
MeSH terms
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Carbazoles / pharmacology
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Cell Culture Techniques
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Cell Line
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Cell Nucleus / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dermatitis, Atopic / metabolism
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Dermatitis, Atopic / pathology*
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Filaggrin Proteins
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Humans
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Interleukin-4 / pharmacology
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Intermediate Filament Proteins / genetics
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Intermediate Filament Proteins / metabolism*
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Protein Precursors / genetics
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Protein Precursors / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Receptors, Aryl Hydrocarbon / agonists
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Receptors, Aryl Hydrocarbon / antagonists & inhibitors
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Receptors, Aryl Hydrocarbon / genetics
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Receptors, Aryl Hydrocarbon / metabolism*
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Tars / pharmacology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transglutaminases / genetics
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Transglutaminases / metabolism
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Up-Regulation / drug effects
Substances
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6-formylindolo(3,2-b)carbazole
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Carbazoles
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DNA-Binding Proteins
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FLG protein, human
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Filaggrin Proteins
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Intermediate Filament Proteins
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Membrane Proteins
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OVOL1 protein, human
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Protein Precursors
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RNA, Small Interfering
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Receptors, Aryl Hydrocarbon
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Tars
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Transcription Factors
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loricrin
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Interleukin-4
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glyteen
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involucrin
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Transglutaminases
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transglutaminase 1