Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan 410011, China.
J Immunol Res. 2022 Jan 22;2022:4542487. doi: 10.1155/2022/4542487. eCollection 2022.
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that is characterized by autoimmunity and its mediated -cell damage. Chronic exposure of -cells to proinflammatory cytokines is known to regulate the expression of many genes, subsequently resulting in the impairment of some signaling pathways involved with insulin production and secretion and/or -cell apoptosis. In our study, RNA sequencing technology was applied to identify differentially expressed mRNAs in MIN6 cells treated with a mix of cytokines, including IL-1, TNF-, and IFN-. The results showed 809 upregulated and 946 downregulated protein-coding mRNAs in MIN6 cells upon the stimulation of cytokines. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses were performed to predict the functions of dysregulated genes. The networks of circRNA-mRNA were constructed between differentially mRNAs and dysregulated expressed circRNAs in our previous study. In addition, we selected 8 dysregulated mRNAs for further validation by quantitative real-time PCR. The RNA sequencing data showed 809 upregulated and 946 downregulated protein-coding mRNAs. GO analysis showed that the top 10 significant "biological processes," "cellular components," and "molecular functions" for upregulated mRNAs include "immune system process," "inflammatory response," and "innate immune response" and the top 10 for downregulated mRNAs include "cell cycle," "mitotic cytokinesis," and "cytoplasm." KEGG analysis showed that these differentially expressed genes were involved with "antigen processing and presentation," "TNF signaling pathway" and "type 1 diabetes," "cell cycle," "necroptosis," and "Rap1 signaling pathway." We also constructed the networks of differentially expressed circRNAs and mRNAs. We observed that upregulated circRNA 006029 and downregulated circRNA 000286 and 017277 were associated with the vast majority of selected dysregulated mRNAs, while circRNA 013053 was only related to the protein-coding gene, . To the summary, these data indicated that differentially expressed mRNAs may play key or partial roles in cytokine-mediated -cell dysfunction and gave us the hint that circRNAs might regulate mRNAs, thereby contributing to the development of T1DM. The current study provided a systematic perspective on the potential functions and possible regulatory mechanisms of mRNAs in proinflammatory cytokine-induced -cell destruction.
1 型糖尿病（T1DM）是一种慢性自身免疫性疾病，其特征为自身免疫和自身免疫介导的β细胞损伤。已知慢性暴露于促炎细胞因子会调节许多基因的表达，进而导致参与胰岛素产生和分泌和/或β细胞凋亡的某些信号通路受损。在我们的研究中，应用 RNA 测序技术鉴定了用包括 IL-1、TNF-α 和 IFN-γ在内的细胞因子混合物处理的 MIN6 细胞中差异表达的 mRNA。结果显示，细胞因子刺激 MIN6 细胞后，有 809 个上调和 946 个下调的蛋白编码 mRNA。进行了基因本体论（GO）和京都基因与基因组百科全书（KEGG）生物途径分析，以预测失调基因的功能。在我们之前的研究中，构建了差异表达的 circRNA-mRNA 网络。此外，我们选择了 8 个失调的 mRNA 通过定量实时 PCR 进一步验证。RNA 测序数据显示，有 809 个上调和 946 个下调的蛋白编码 mRNA。GO 分析显示，上调 mRNA 的前 10 个显著“生物学过程”、“细胞成分”和“分子功能”包括“免疫系统过程”、“炎症反应”和“固有免疫反应”，下调 mRNA 的前 10 个包括“细胞周期”、“有丝分裂细胞分裂”和“细胞质”。KEGG 分析表明，这些差异表达的基因参与“抗原加工和呈递”、“TNF 信号通路”和“1 型糖尿病”、“细胞周期”、“坏死性凋亡”和“Rap1 信号通路”。我们还构建了差异表达 circRNA 和 mRNA 的网络。我们观察到上调的 circRNA 006029 和下调的 circRNA 000286 和 017277 与大多数选定的失调 mRNA 相关，而 circRNA 013053 仅与蛋白编码基因有关。总之，这些数据表明差异表达的 mRNA 可能在细胞因子介导的β细胞功能障碍中发挥关键或部分作用，并提示 circRNA 可能通过调节 mRNA 从而有助于 1 型糖尿病的发生。本研究从系统的角度阐述了促炎细胞因子诱导的β细胞破坏中差异表达的 mRNA 的潜在功能和可能的调控机制。
