Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to structurally diverse synthetic and naturally occurring chemicals including dioxins, flavonoids, tryptophan photoproducts, and Malassezia metabolites. Upon binding to its ligands, cytoplasmic AhR translocates to the nucleus, heterodimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological and toxicological effects by inducing the transcription of various AhR-responsive genes. AhR ligation controls oxidation/antioxidation, epidermal barrier function, photo-induced response, melanogenesis, and innate immunity. This review summarizes recent advances in the understanding of the regulatory mechanisms of skin homeostasis mediated by the AhR/ARNT system.

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BackgroundDespite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.MethodsOverall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.ResultsWe confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).ConclusionsGenotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1486-7) contains supplementary material, which is available to authorized users.

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.

Ketoconazole (KCZ) has been shown to exhibit anti-inflammatory effects in addition to its inhibitory effects against fungi; however, the underlying molecular mechanism remains poorly understood. Aryl hydrocarbon receptor (AhR), a receptor that is activated by polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons such as dioxin, is a sensor of the redox system against oxidative stress and regulates nuclear factor-erythroid 2-related factor-2 (Nrf2), a master switch of the redox machinery. To clarify whether KCZ modulates AhR-Nrf2 function leading to redox system activation, cultured human keratinocytes were treated with KCZ. Confocal microscopic analysis revealed that KCZ induced AhR nuclear translocation, resulting in the upregulation of CYP1A1 mRNA and protein expression. Furthermore, KCZ actively switched on Nrf2 nuclear translocation and quinone oxidoreductase 1 expression. Tumor necrosis factor-α- and benzo(a)pyrene (BaP)-induced reactive oxidative species (ROS) and IL-8 production were effectively inhibited by KCZ. Knockdown of either AhR or Nrf2 abolished the inhibitory capacity of KCZ on ROS and IL-8 production. In addition, KCZ-induced Nrf2 activation was canceled by AhR knockdown. Moreover, KCZ inhibited BaP-induced 8-hydroxydeoxyguanosine and IL-8 production. In conclusion, the engagement of AhR by KCZ exhibits the cytoprotective effect mediated by the Nrf2 redox system, which potently downregulates either cytokine-induced (AhR-independent) or PAH-induced (AhR-dependent) oxidative stress.