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IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis.

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.

SUBMITTER: Vu YH

PROVIDER: S-EPMC7764126 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis.

Vu Yen Hai YH Hashimoto-Hachiya Akiko A Takemura Masaki M Yumine Ayako A Mitamura Yasutaka Y Nakahara Takeshi T Furue Masutaka M Tsuji Gaku G

International journal of molecular sciences 20201210 24

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-treat ...[more]

PMID: 33321923

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Project description:ImportanceTopical calcineurin inhibitors (TCIs), primarily used to treat atopic dermatitis (AD), carry a black box label warning users about the potential for increased skin cancer risk. The risk associated with keratinocyte carcinoma (KC), the most common cancer, defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), remains poorly defined because findings from large-scale postmarketing surveillance studies have not been reported.ObjectivesTo examine KC risk overall and by subtype (BCC and SCC) among adults with AD exposed to TCIs compared with those exposed to topical corticosteroids (primary comparator group) and those unexposed to TCIs or topical corticosteroids (alternative comparator group) as well as alterations in risk with TCI dose, frequency, and duration of exposure.Design, setting, and participantsA retrospective cohort study was conducted at Kaiser Permanente Northern California, a large, integrated health care delivery system, of adults 40 years or older (n = 93 746) with a physician-rendered diagnosis of AD or dermatitis. Patients who were diagnosed from January 1, 2002, to December 31, 2013, were included, with follow-up through December 31, 2017. Data analysis was conducted from June 1, 2016, to October 1, 2018.ExposuresTime-varying pharmacy-dispensed TCI exposure (n = 7033) over the study period was compared with topical corticosteroids (n = 73 674) and no TCI or topical corticosteroid exposure (n = 46 141).Main outcomes and measuresElectronic pathologic testing-validated incident KCs (n = 7744).ResultsAmong a cohort of 93 746 members, the mean (SD) age was 58.5 (12.7) years, and 55 023 patients (58.7%) were women. Multivariable Cox proportional hazards regression revealed no association between TCI exposure and KC risk (adjusted hazard ratio [aHR], 1.02; 95% CI, 0.93-1.13) compared with topical corticosteroid exposure. Similarly, there were no significant differences in BCC risk (aHR, 1.01; 95% CI, 0.90-1.14, TCI vs topical corticosteroids) or SCC risk (aHR, 0.94; 95% CI, 0.82-1.08, TCI vs topical corticosteroids). Changing the comparator group to unexposed individuals yielded similar findings (aHR, 1.04; 95% CI, 0.91-1.19, TCI vs unexposed for basal cell carcinoma). There were no associations between TCI dose, frequency, and duration of use and BCC, SCC, or overall KC risk.Conclusions and relevanceThe results of this postmarketing surveillance study of adult health plan members with AD revealed no apparent association between TCI exposure and overall KC, BCC, or SCC risk. Secondary analyses examining dose, frequency, and duration of TCI exposure revealed no associations. These findings suggest that use of TCIs may be safe with respect to KC risk among adults with AD.

Dataset Information

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis.

Publications

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis.

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