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CYT387, a Novel JAK2 Inhibitor, Suppresses IL-13-Induced Epidermal Barrier Dysfunction Via miR-143 Targeting IL-13Rα1 and STAT3

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Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease influencing not only children but also adults. It is well-known that AD has a complex pathogenesis without effective therapy. Herein, we explored the function and mechanism of CYT387, a novel JAK2 inhibitor, on epidermal barrier damage. HaCaT cells exposed with high-concentration Ca2+ (1.8 mM) for 14 days were recruited for the model of keratinocytes (KC). The cell model of skin barrier damage was induced by IL-13, and KC markers such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL) were detected to judge the success of the model. In this study, we found that miR-143 was lowly expressed whereas IL-13Rα1 was highly expressed in blood cells of patients with AD, indicating their negative correlation. Moreover, IL-13 treatment down-regulated miR-143 and up-regulated activated JAK2 and STAT3 phosphorylation, which was reversed by CYT387 administration. The dual-luciferase reporter assay verified that miR-143 could directly bind to 3′-UTR of IL-13Rα1, as well as STAT3. Furthermore, the function of CYT387 in the skin barrier damage induced by IL-13 was abolished by miR-143 inhibitor. Thus, CYT387 might alleviate IL-13-induced epidermal barrier damage via targeting IL-13Rα1 and STAT3 by miR-143 to repress inflammation. These findings revealed that the protective effects and the underlying mechanisms of CYT387 in AD, which provided evidence that miR-143 may be a novel therapeutic target for AD.

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Data Availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Funding

This work was supported by Excellent talent project of Organization Department of Beijing Municipal Party committee and Outstanding youth talents project of North University of Technology.

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Authors and Affiliations

  1. School of Mechanical and Material Engineering, North China University of Technology, No. 5 Jinyuanzhuang Road, Shijingshan District, Beijing, 100144, People’s Republic of China

    Yan Zu, Qiang Li & Shu-Ting Zhang

  2. Beijing Institute of Astronautical System Engineering, Beijing, 10076, People’s Republic of China

    Xiao-Fei Chen

Authors
  1. Yan Zu
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  2. Xiao-Fei Chen
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  3. Qiang Li
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  4. Shu-Ting Zhang
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Contributions

Guarantor of integrity of the entire study: YZ; study concepts: YZ; study design: YZ; definition of intellectual content: XFC, QL; literature research: S-TZ; clinical studies: X-FC, S-TZ; experimental studies: YZ, W-TL; data acquisition: YZ, X-FC; data analysis: YZ, S-TZ; statistical analysis: YZ, S-TZ; manuscript preparation: YZ, W-TL; manuscript editing: YZ; manuscript review: YZ.

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Correspondence to Yan Zu.

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The use of all samples in this article was approved by the Ethics Committee of Peking Union Medical College Hospital.

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10528_2020_10003_MOESM1_ESM.tif

Supplementary Fig. 1 A. Western blot analysis of pSTAT6 and STAT6, β-actin was used as internal control. After construction of the KC model, IL-13 (10 ng/mL) was administrated for inducing skin barrier damage, and cells were collected to analyze by western blot assay. B. qRT-PCR assay was performed to detect the expression of IL-13Rα2 and IL-4Rα after transfection of miR-143 mimics or inhibitor and their negative controls. N.S., no significance. (TIF 4116 kb)

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Zu, Y., Chen, XF., Li, Q. et al. CYT387, a Novel JAK2 Inhibitor, Suppresses IL-13-Induced Epidermal Barrier Dysfunction Via miR-143 Targeting IL-13Rα1 and STAT3. Biochem Genet 59, 531–546 (2021). https://doi.org/10.1007/s10528-020-10003-0

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  • DOI: https://doi.org/10.1007/s10528-020-10003-0

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