IL-24 negatively regulates keratinocyte differentiation induced by tapinarof, an aryl hydrocarbon receptor modulator: Implication in the treatment of atopic dermatitis

Yen Hai Vu, Akiko Hashimoto-Hachiya, Masaki Takemura, Ayako Yumine, Yasutaka Mitamura, Takeshi Nakahara, Masutaka Furue, Gaku Tsuji

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.

Original languageEnglish
Article number9412
Pages (from-to)1-16
Number of pages16
JournalInternational journal of molecular sciences
Volume21
Issue number24
DOIs
Publication statusPublished - Dec 2 2020

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'IL-24 negatively regulates keratinocyte differentiation induced by tapinarof, an aryl hydrocarbon receptor modulator: Implication in the treatment of atopic dermatitis'. Together they form a unique fingerprint.

Cite this