title: 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
  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.
authors.affiliation: Department of Dermatology, Kyushu University, Fukuoka, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Takei
authors.forename: Chikage
authors.initials: C
authors.lastname: Mitoma
authors.forename: Akiko
authors.initials: A
authors.lastname: Hashimoto-Hachiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takahara
authors.forename: Gaku
authors.initials: G
authors.lastname: Tsuji
authors.forename: Makiko
authors.initials: M
authors.lastname: Kido-Nakahara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakahara
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000235:genetics; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D000091344:Filaggrin Proteins; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D015603:Keratinocytes; D008565:Membrane Proteins / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013638:Tars / Q000494:pharmacology*; D018418:Th2 Cells / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002135:Calcium-Binding Proteins; D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C503908:HRNR protein, human; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011498:Protein Precursors; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D013638:Tars; D014409:Tumor Necrosis Factor-alpha; C064554:loricrin; D001564:Benzo(a)pyrene; C007876:glyteen; C032253:involucrin; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Glyteer; aryl hydrocarbon receptor; filaggrin; nuclear factor-erythroid 2-related factor-2; reactive oxygen species; soybean tar