Temporal transcriptome analysis of the endothelial response to tumour necrosis factor

Abstract

ABSTRACTThe vascular endothelium acts as a dynamic interface between blood and tissue and provides an anti-inflammatory and anti-thrombotic surface under normal conditions. Tumour necrosis factor-α (TNF), a cytokine that drives acute and chronic inflammation, induces numerous transcriptional changes in endothelial cells (EC). However, the overall temporal dynamics of this response have not been fully elucidated. Here, we conducted an extended time-course analysis of the EC response to TNF, from 30 minutes to 72 hours. We identified TNF-regulated genes and used weighted gene correlation network analysis (WGCNA) to decipher co-expression profiles, uncovering two distinct temporal phases - an acute response initiated between 1-4 hours, followed by a later phase initiated between 12-24 hours. Several previously uncharacterised genes were strongly regulated during the acute phase, while the majority in the later phase were interferon-stimulated genes (ISGs). A lack of interferon transcription indicated that this TNF-induced ISG expression was independent ofde novointerferon production and autocrine signalling. Furthermore, we observed two different groups of genes whose transcription was inhibited by TNF, those that resolved towards baseline levels over time, and those that did not. Our study provides insights into the global temporal dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. These findings may be useful in understanding the role of EC in inflammation and developing TNF signalling-targeting therapies.