Department of Dermatology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
Aging (Albany NY). 2021 Aug 10;13(15):19293-19305. doi: 10.18632/aging.203265.
Skin tissue is the natural barrier that protects our body, the damage of which can be repaired by the epidermal stem cells (ESCs). However, external factors abolish the self-repair ability of ESCs by inducing oxidative stress and severe inflammation. Apremilast is a small molecular inhibitor of phosphodiesterase 4 that was approved for the treatment of psoriasis. In the present study, the protective property of Apremilast against IL-1α-induced dysfunction on epidermal stem cells, as well as the preliminary mechanism, will be investigated.
ESCs were isolated from neonatal mice. The expression levels of TNF-α, IL-8, IL-12, MMP-2, and MMP-9 were detected using real-time PCR and ELISA. MitoSOX Red assay was used to determine the level of mitochondrial reactive oxygen species (ROS). Western blot and real-time PCR were utilized to determine the expression levels of IL-1R1, Myd88, and TRAF6. Activation of NF-κB was assessed by measuring the p-NF-κB p65 and luciferase activity. Capacities of ESCs were evaluated by measuring the gene expressions of integrin β1 and Krt19 using real-time PCR.
Firstly, the expression levels of TNF-α, IL-8, IL-12, MMP-2, MMP-9 and IL-1R1, as well as the ROS level, were significantly elevated by IL-1α but greatly suppressed by treatment with Apremilast. Subsequently, we found that the activated Myd88/TRAF6/NF-κB signaling pathway induced by stimulation with IL-1α was significantly inhibited by the introduction of Apremilast. As a result, Apremilast protected ESCs against IL-1α-induced impairment in capacities of ESCs, this was verified by the elevated expression levels of integrin β1 and Krt19.
Apremilast might ameliorate IL-1α-induced dysfunction in ESCs by mitigating oxidative stress and inflammation through inhibiting the activation of the Myd88/TRAF6/NF-κB signaling pathway.
皮肤组织是保护我们身体的天然屏障，其损伤可以由表皮干细胞（ESCs）修复。然而，外部因素通过诱导氧化应激和严重炎症来破坏 ESCs 的自我修复能力。阿普米司特是一种磷酸二酯酶 4 的小分子抑制剂，已被批准用于治疗银屑病。本研究旨在探讨阿普米司特对白细胞介素 1α（IL-1α）诱导的表皮干细胞功能障碍的保护作用及其初步机制。
从新生小鼠中分离 ESCs。采用实时 PCR 和 ELISA 检测 TNF-α、IL-8、IL-12、MMP-2 和 MMP-9 的表达水平。采用 MitoSOX Red 测定线粒体活性氧（ROS）水平。Western blot 和实时 PCR 用于检测 IL-1R1、Myd88 和 TRAF6 的表达水平。通过测量 p-NF-κB p65 和荧光素酶活性来评估 NF-κB 的激活。通过实时 PCR 测量整合素β1 和 Krt19 的基因表达来评估 ESCs 的功能。
首先，IL-1α显著上调了 TNF-α、IL-8、IL-12、MMP-2、MMP-9 和 IL-1R1 的表达水平以及 ROS 水平，而阿普米司特处理则显著抑制了这些变化。随后，我们发现，IL-1α 刺激引起的激活的 Myd88/TRAF6/NF-κB 信号通路被阿普米司特的引入显著抑制。结果，阿普米司特通过抑制 Myd88/TRAF6/NF-κB 信号通路的激活，保护 ESCs 免受 IL-1α 诱导的功能障碍，这通过整合素β1 和 Krt19 的表达水平升高得到验证。
阿普米司特可能通过减轻氧化应激和炎症，通过抑制 Myd88/TRAF6/NF-κB 信号通路的激活，改善 IL-1α 诱导的 ESCs 功能障碍。
