Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: The basis of its anti-inflammatory effect

Gaku Tsuji, Masakazu Takahara, Uchi Hiroshi, Tetsuo Matsuda, Takahito Chiba, Satoshi Takeuchi, Fumiko Yasukawa, Yoichi Moroi, Masutaka Furue

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)59-68
Number of pages10
JournalJournal of Investigative Dermatology
Volume132
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

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Aryl Hydrocarbon Receptors
Ketoconazole
Keratinocytes
Anti-Inflammatory Agents
Oxidation-Reduction
Interleukin-8
Oxidative stress
Polycyclic Aromatic Hydrocarbons
Oxidative Stress
Chemical activation
Halogenated Hydrocarbons
Aromatic Hydrocarbons
Cytochrome P-450 CYP1A1
Dioxins
Benzo(a)pyrene
Fungi
Machinery
Oxidoreductases
Up-Regulation
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes : The basis of its anti-inflammatory effect. / Tsuji, Gaku; Takahara, Masakazu; Hiroshi, Uchi; Matsuda, Tetsuo; Chiba, Takahito; Takeuchi, Satoshi; Yasukawa, Fumiko; Moroi, Yoichi; Furue, Masutaka.

In: Journal of Investigative Dermatology, Vol. 132, No. 1, 01.01.2012, p. 59-68.

Research output: Contribution to journalArticle

Tsuji, Gaku ; Takahara, Masakazu ; Hiroshi, Uchi ; Matsuda, Tetsuo ; Chiba, Takahito ; Takeuchi, Satoshi ; Yasukawa, Fumiko ; Moroi, Yoichi ; Furue, Masutaka. / Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes : The basis of its anti-inflammatory effect. In: Journal of Investigative Dermatology. 2012 ; Vol. 132, No. 1. pp. 59-68.
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