Antioxidant soybean tar <scp>G</scp>lyteer rescues <scp>T</scp>‐helper‐mediated downregulation of filaggrin expression via aryl hydrocarbon receptor

Abstract

Abstract Soybean tar G lyteer ( G ly) has been widely used for the treatment of various inflammatory skin diseases in J apan since 1924 as an alternative to coal tar remedy. Recently, coal tar has been shown to induce barrier repair in atopic dermatitis via aryl hydrocarbon receptor ( A h R ). In this study, we demonstrated that G ly activated A h R by inducing its cytoplasmic to nuclear translocation in keratinocytes. The A h R ligation by G ly was biologically active, with significant and dose‐dependent upregulation of CYP 1 A 1 expression, which is a specific marker for A h R activation. Gly upregulated the expression of filaggrin in an A h R ‐dependent manner because its enhancing effect was completely abrogated in A h R ‐knockdown keratinocytes. T ‐helper ( T h)2 cytokines inhibited the expression of filaggrin; however, G ly completely restored the T h2‐mediated inhibition of filaggrin expression. Furthermore, G ly coordinately upregulated a series of epidermal differentiation complex genes, including involucrin, loricrin and hornerin. In addition, G ly exhibited potent antioxidant activity through the activation of nuclear factor‐erythroid 2‐related factor‐2 ( N rf2) and downstream antioxidant enzymes such as NAD (P) H :quinone oxidoreductase 1 ( N qo1), which actually inhibited the generation of reactive oxygen species in keratinocytes treated with tumor necrosis factor‐α or benzo[α]pyrene. In conclusion, antioxidant G ly rescues the downregulated expression of filaggrin (and plausibly other barrier proteins) in a T h2‐skewed milieu via A h R activation, which may partly explain its empirical anti‐inflammatory therapeutic effects.