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The AhR-Nrf2 pathway in keratinocytes: on the road to chemoprevention?

Thomas Haarmann-Stemmann1, Josef Abel, Ellen Fritsche

  • 1Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.

The Journal of Investigative Dermatology
|December 14, 2011
PubMed

Insights

The antifungal drug ketoconazole activates the Aryl hydrocarbon receptor (AhR) and the Nrf2 antioxidant pathway in skin cells. This AhR-Nrf2 signaling protects against oxidative stress, offering new avenues for treating inflammatory skin conditions.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Toxicology

Background:

  • The Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the skin's response to environmental stressors.
  • Understanding pathways that regulate skin homeostasis and defense is crucial for preventive medicine.

Purpose of the Study:

  • To investigate the effects of the antifungal agent ketoconazole on AhR signaling and antioxidant responses in human keratinocytes.
  • To elucidate the role of AhR in mediating ketoconazole-induced cytoprotective effects against oxidative stress.

Main Methods:

  • Human keratinocytes were treated with ketoconazole.
  • AhR signaling activation was assessed.
  • Nrf2 nuclear translocation was measured.
  • Cytoprotective effects against oxidative stress were evaluated in an AhR-dependent manner.

Main Results:

  • Ketoconazole was identified as an inducer of AhR signaling in human keratinocytes.
  • Ketoconazole also stimulated the Nrf2 antioxidant response.
  • The nuclear translocation of Nrf2 and its protective effects against oxidative stress were dependent on a functional AhR.
  • A novel AhR-Nrf2 pathway was identified.

Conclusions:

  • Ketoconazole activates a previously unrecognized AhR-Nrf2 pathway in keratinocytes.
  • This pathway confers cytoprotection against oxidative stress.
  • The findings suggest potential therapeutic strategies for inflammatory skin diseases by targeting the AhR-Nrf2 axis.

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