School of Mechanical and Material Engineering, North China University of Technology, No. 5 Jinyuanzhuang Road, Shijingshan District, Beijing, 100144, People's Republic of China.
Beijing Institute of Astronautical System Engineering, Beijing, 10076, People's Republic of China.
Biochem Genet. 2021 Apr;59(2):531-546. doi: 10.1007/s10528-020-10003-0. Epub 2020 Nov 15.
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 Ca (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.
特应性皮炎（AD）是一种影响儿童和成人的慢性炎症性皮肤病。众所周知，AD 的发病机制复杂，目前尚无有效的治疗方法。在此，我们探讨了新型 JAK2 抑制剂 CYT387 对表皮屏障损伤的作用和机制。我们招募了用高浓度 Ca（1.8 mM）孵育 14 天的 HaCaT 细胞来建立角质形成细胞（KC）模型。用 IL-13 诱导皮肤屏障损伤细胞模型，检测 FLG、LOR 和 IVL 等 KC 标志物，以判断模型是否成功。在这项研究中，我们发现 AD 患者的血液细胞中 miR-143 表达水平较低，而 IL-13Rα1 表达水平较高，表明它们呈负相关。此外，IL-13 处理下调了 miR-143，而上调了激活的 JAK2 和 STAT3 磷酸化，这一过程可被 CYT387 逆转。双荧光素酶报告基因检测证实 miR-143 可直接与 IL-13Rα1 和 STAT3 的 3'-UTR 结合。此外，miR-143 抑制剂可消除 CYT387 在 IL-13 诱导的皮肤屏障损伤中的作用。因此，CYT387 可能通过 miR-143 靶向 IL-13Rα1 和 STAT3 抑制炎症来减轻 IL-13 诱导的表皮屏障损伤。这些发现揭示了 CYT387 在 AD 中的保护作用及其潜在机制，为 miR-143 可能成为 AD 的一种新的治疗靶点提供了证据。
