MDM2 通过靶向 p53 来维持上皮细胞的平衡。

IF 4.7 3区 医学 Q2 IMMUNOLOGY
Journal of Innate Immunity Pub Date : 2024-01-01 Epub Date: 2024-08-12 DOI:10.1159/000539824
Su Wang, Shufen Zhong, Ying Huang, Songling Zhu, Shuangfeng Chen, Ran Wang, Sonam Wangmo, Bo Peng, Houkun Lv, Jichao Yang, Liyan Ma, Zhiyang Ling, Yaguang Zhang, Pengfei Sui, Bing Sun
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引用次数: 0

摘要

引言众所周知,MDM2 是 p53 的主要负调控因子,MDM2 通过依赖 p53 和不依赖 p53 的途径促进肺癌纤维化和肺损伤。然而,MDM2影响哮喘发病机制的机制尚不清楚。在本研究中,我们研究了MDM2在2型肺部炎症中肺部上皮细胞的功能:方法:我们利用 II 型肺泡上皮细胞特异性杂合子敲除 Mdm2 小鼠来验证其功能。然后建立木瓜蛋白酶诱导的哮喘模型,通过免疫组化和流式细胞术分析观察炎症的变化:结果:本研究敲除了 2 型肺泡上皮细胞中的小鼠 Mdm2 基因。结果:本研究敲除了小鼠 2 型肺泡上皮细胞中的 Mdm2 基因,结果表明,杂合子 Mdm2 基因缺失小鼠极易受蛋白酶过敏原木瓜蛋白酶诱导的肺部炎症影响,其特征是 ILC2 数量、IL-5 和 IL-13 细胞因子水平以及肺部病理变化增加。一项机理研究表明,肺上皮细胞和 A549 细胞系中的 Mdm2 表达减少后,p53 被过度激活,其下游基因 p21、Puma 和 Noxa 的表达升高,导致细胞凋亡。Mdm2敲除后,炎症相关基因IL-25、HMGB1和TNF-α的mRNA表达增加,进一步扩大了下游ILC2反应和肺部炎症:这些结果表明,Mdm2通过靶向P53维持肺上皮细胞的平衡,并调控2型肺炎症下肺上皮细胞的功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MDM2 Is Essential to Maintain the Homeostasis of Epithelial Cells by Targeting p53.

Introduction: MDM2 is known as the primary negative regulator of p53, and MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation.

Methods: We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis.

Results: In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1, and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation.

Conclusion: These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53 and regulates the function of lung epithelial cells under type 2 lung inflammation.

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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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