ArticleInternational journal of molecular sciences2024
Difamilast, a Topical Phosphodiesterase 4 Inhibitor, Produces Soluble ST2 via the AHR-NRF2 Axis in Human Keratinocytes.
Article in International journal of molecular sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- PDE4 Inhibition in Dermatologic Disease: Impacts Beyond Inflammation.International journal of dermatology · 2026Review
- From Barrier Disruption and Immune Dysregulation to Targeted Therapies in Atopic Dermatitis.Clinical reviews in allergy & immunology · 2026Review
- Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential.Pharmacological reviews · 2026Review
- AHR/NRF2 Dual Agonist Prediction and Natural Compound Screening Based on Machine Learning: A New Strategy for the Treatment of Atopic Dermatitis.International journal of molecular sciences · 2026Article
- The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation.Nature reviews. Drug discovery · 2025Review
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Authors and funding
7 authors.
Funding
Abstract
Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)-nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR-NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.
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