The antimycotic drug liranaftate has been shown to have anti-inflammatory effects, but its mechanism of action is largely unknown. Many polycyclic aromatic hydrocarbons and other external chemicals bind to the cytosolic aryl hydrocarbon receptor (AhR), which is abundantly expressed in cultured human keratinocytes. Liranaftate induced nuclear translocation of AhR and nuclear factor-erythroid 2-related factor-2 (Nrf2) from the cytoplasm in the keratinocytes and upregulated mRNA for NAD(P)H : quinone oxidoreductase 1 (Nqo1) and Nrf2. TNFα-induced reactive oxidative species (ROS) and IL-8 production were effectively inhibited by liranaftate. Knockdown of AhR abolished liranaftate-induced Nqo1 and Nrf2 expressions as well as the inhibitory action on IL-8 production, suggesting an AhR-dependent mechanism of action. Additionally, liranaftate upregulated the mRNA expressions of skin barrier proteins such as filaggrin, loricrin and involucrin in an AhR-dependent fashion. These anti-inflammatory effects may partly explain the rapid and potent clinical efficacy against tinea by liranaftate.
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