Difamilast, a Topical Phosphodiesterase 4 Inhibitor, Produces Soluble ST2 via the AHR-NRF2 Axis in Human Keratinocytes

• Published in: International journal of molecular sciences Vol. 25; no. 14; p. 7910
• Main Authors: Tsuji, Gaku, Yumine, Ayako, Kawamura, Koji, Takemura, Masaki, Kido-Nakahara, Makiko, Yamamura, Kazuhiko, Nakahara, Takeshi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2024
• Subjects: Advertising executives; aryl hydrocarbon receptor; Atopic dermatitis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Line; Cellular signal transduction; Drug therapy; Ethylenediaminetetraacetic acid; Humans; IL-33; Inflammation; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33 - metabolism; Keratinocytes - drug effects; Keratinocytes - metabolism; Kinases; NF-E2-Related Factor 2 - metabolism; nuclear factor erythroid 2-related factor 2; Pathogenesis; phosphodiesterase 4; Phosphodiesterase 4 Inhibitors - pharmacology; Phosphorylation; Proteins; Pruritus; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - metabolism; RNA; Roflumilast; Scientific equipment and supplies industry; Signal Transduction - drug effects; soluble ST2; United States; Japan; atopic dermatitis; phosphodiesterase 4; IL-33; nuclear factor erythroid 2-related factor 2; soluble ST2; aryl hydrocarbon receptor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25147910

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.