Antioxidant soybean tar Glyteer rescues T‐helper‐mediated downregulation of filaggrin expression via aryl hydrocarbon receptor

Abstract

Soybean tar Glyteer (Gly) has been widely used for the treatment of various inflammatory skin diseases in Japan 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 (AhR). In this study, we demonstrated that Gly activated AhR by inducing its cytoplasmic to nuclear translocation in keratinocytes. The AhR ligation by Gly was biologically active, with significant and dose-dependent upregulation of CYP1A1 expression, which is a specific marker for AhR activation. Gly upregulated the expression of filaggrin in an AhR-dependent manner because its enhancing effect was completely abrogated in AhR-knockdown keratinocytes. T-helper (Th)2 cytokines inhibited the expression of filaggrin; however, Gly completely restored the Th2-mediated inhibition of filaggrin expression. Furthermore, Gly coordinately upregulated a series of epidermal differentiation complex genes, including involucrin, loricrin and hornerin. In addition, Gly exhibited potent antioxidant activity through the activation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and downstream antioxidant enzymes such as NAD(P)H:quinone oxidoreductase 1 (Nqo1), which actually inhibited the generation of reactive oxygen species in keratinocytes treated with tumor necrosis factor-α or benzo[α]pyrene. In conclusion, antioxidant Gly rescues the downregulated expression of filaggrin (and plausibly other barrier proteins) in a Th2-skewed milieu via AhR activation, which may partly explain its empirical anti-inflammatory therapeutic effects.

Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2

“…Various phytochemicals and herbal extracts exert their antioxidant properties by activating the NRF2 system in an AHR-dependent or AHR-independent manner in human epidermal keratinocytes [18,19,20,21,22]. Certain antioxidant phytochemicals also upregulate the expression of filaggrin (FLG), which plays a pivotal role in maintaining epidermal barrier function [19,20,21,23].…”

146 Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis

“…7,21 Our previous study has shown that steady-state OVOL1 expression is primarily present in the cytoplasm of NHEKs. 18 Ketoconazole, a potent AHR ligand, induces nuclear translocation of OVOL1 in NHEKs.…”

“…These results indicate that FICZ and Glyteer upregulate FLG via the AHR − OVOL1 axis in NHEKs. Because the monolayer-cultured NHEKs system was difficult to use for evaluation of protein expression of FLG, including profilaggrin expression, 7 we utilized three-dimensionally (3D) cultured NHEKs. In the western blot analysis, FICZ and Glyteer yielded increased OVOL1 and FLG protein expression, which was normalized by CH-223191, a specific antagonist of AHR (Figure 3l).…”

“…7,21 It has been shown in AHR knockdown NHEKs 21 that an AHR-binding site (xenobiotic response element) in the FLG promoter region has an important role in the upregulation of FLG induced by AHR activation. Nevertheless, we next revealed that the upregulation of FLG induced by AHR activation was abrogated in either AHR knockdown or OVOL1-knockdown NHEKs.…”

“…6,7 Activated AHR relocates from the cytoplasm to nucleus, and this action induces transcription of the target genes, such as CYP1A1, in NHEKs. Nonetheless, the precise mechanism by which AHR regulates FLG expression remains unclear.…”