miRNA let-7b 通过靶向银屑病中 IL-6 介导的 ERK 信号通路抑制角质形成细胞分化。
MicroRNA let-7b inhibits keratinocyte differentiation by targeting IL-6 mediated ERK signaling in psoriasis.
机构信息
The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, college of Bioengineering, Chongqing University, Chongqing, 400044, China.
Department of Dermatology, Chongqing First People's Hospital and Chongqing Traditional Chinese Medicine Hospital, No. 40 Daomenkou St., District Yuzhong, Chongqing, 400011, China.
出版信息
Cell Commun Signal. 2018 Sep 15;16(1):58. doi: 10.1186/s12964-018-0271-9.
BACKGROUND
The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. This study aimed to explore the effects of IL-6 targeting by let-7b and ERK1/2 mediated signaling on keratinocyte differentiation in psoriasis.
METHODS
Following imiquimod cream (IMQ) application to let-7b (keratinocyte-specific let-7b overexpression mouse) and control mice for 7 days, we analyzed erythema, scaling and thickening of skin. A dual luciferase reporter assay and bioinformatics was carried out to detect target gene of let-7b. Additionally, the differentiation markers were measured. Immunohistochemistry analyses demonstrate a relationship of let-7b with IL-6 and ERK signaling.
RESULTS
we found let-7b inhibits acanthosis and reduces the disease severity by treatment with IMQ compared to wild-type mice. Further study illustrated that let-7b promotes differentiation of keratinocytes in vivo and in vitro. Using bioinformatics and reporter gene assays, we found that IL-6 is a target gene of let-7b. In psoriasis, high expression levels of IL-6 lead to increased acivation of p-ERK1/2. High levels of let-7b transgene expression suppresses IL-6 expression and leads to increased keratinocyte differentiation. Moreover, let-7b acts as an upstream negative regulator of the ERK signaling pathway in keratinocytes of psoriasis.
CONCLUSIONS
Our result reveals a previously unknown mechanism for regulation of IL-6 levels during psoriasis by let-7b and highlights a critical role for the ERK1/2 signaling pathway in epidermal differentiation during psoriasis.
TRIAL REGISTRATION
The ethical approval for this study was from the Affiliated Hospital of Medical University of Anhui _ Fast_ PJ2017-11-14.
背景
大量研究表明微小 RNA（miRNA）广泛参与银屑病的病理生理学过程。然而，为了使这些信息能够在治疗性地调控 miRNA 水平方面发挥作用，阐明其详细的功能机制至关重要。本研究旨在探讨白细胞介素 6（IL-6）靶向治疗对银屑病角质形成细胞分化的影响。
方法
我们在咪喹莫特乳膏（IMQ）处理 let-7b（角质形成细胞特异性 let-7b 过表达小鼠）和对照小鼠 7 天后，分析皮肤红斑、鳞屑和增厚。通过双荧光素酶报告基因检测和生物信息学分析，检测 let-7b 的靶基因。此外，还检测了分化标志物。免疫组织化学分析表明 let-7b 与 IL-6 和 ERK 信号通路之间存在相关性。
结果
与野生型小鼠相比，let-7b 可抑制银屑病角质形成细胞过度增生，减轻疾病严重程度。进一步研究表明，let-7b 可促进角质形成细胞在体内和体外的分化。通过生物信息学和报告基因检测，我们发现 IL-6 是 let-7b 的靶基因。在银屑病中，IL-6 的高表达水平导致 p-ERK1/2 的过度激活。高水平的 let-7b 转基因表达抑制了 IL-6 的表达，导致角质形成细胞分化增加。此外，let-7b 在银屑病角质形成细胞中作为 ERK 信号通路的上游负调控因子发挥作用。
结论
本研究揭示了 let-7b 调控银屑病中 IL-6 水平的未知机制，并强调了 ERK1/2 信号通路在银屑病表皮分化中的关键作用。
试验注册
本研究的伦理批准来自安徽医科大学附属医院 _ Fast_ PJ2017-11-14。
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