Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway.
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
J Immunol. 2024 Jan 1;212(1):117-129. doi: 10.4049/jimmunol.2300419.
The vascular endothelium acts as a dynamic interface between blood and tissue. TNF-α, a major regulator of inflammation, induces endothelial cell (EC) transcriptional changes, the overall response dynamics of which have not been fully elucidated. In the present study, we conducted an extended time-course analysis of the human EC response to TNF, from 30 min to 72 h. We identified regulated genes and used weighted gene network correlation analysis to decipher coexpression profiles, uncovering two distinct temporal phases: an acute response (between 1 and 4 h) and a later phase (between 12 and 24 h). Sex-based subset analysis revealed that the response was comparable between female and male cells. Several previously uncharacterized genes were strongly regulated during the acute phase, whereas the majority in the later phase were IFN-stimulated genes. A lack of IFN transcription indicated that this IFN-stimulated gene expression was independent of de novo IFN production. We also observed two groups of genes whose transcription was inhibited by TNF: those that resolved toward baseline levels and those that did not. Our study provides insights into the global dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. Data for all coding and noncoding genes is provided on the Web site (http://www.endothelial-response.org/). These findings may be useful in understanding the role of ECs in inflammation and in developing TNF signaling-targeted therapies.
血管内皮作为血液和组织之间的动态界面发挥作用。TNF-α 是炎症的主要调节因子，可诱导内皮细胞 (EC) 的转录变化，但尚未完全阐明其整体反应动力学。在本研究中，我们对 TNF 诱导的人 EC 反应进行了扩展的时间过程分析，从 30 分钟到 72 小时。我们鉴定了受调控的基因，并使用加权基因网络相关分析来破译共表达谱，揭示了两个不同的时相：急性反应（1 至 4 小时）和后期（12 至 24 小时）。基于性别的亚群分析表明，女性和男性细胞的反应相似。在急性相期间强烈调节了几个以前未表征的基因，而在后期相时大多数是 IFN 刺激的基因。缺乏 IFN 转录表明，这种 IFN 刺激的基因表达独立于从头 IFN 产生。我们还观察到两组基因的转录受到 TNF 抑制：那些趋于基线水平的基因和那些不抑制的基因。我们的研究提供了对 TNF 诱导的 EC 转录反应的全局动力学的深入了解，突出了急性和后期阶段的不同基因表达模式。有关所有编码和非编码基因的数据都可在网站上获得（http://www.endothelial-response.org/）。这些发现可能有助于理解 EC 在炎症中的作用，并开发针对 TNF 信号的靶向治疗方法。
