5 research outputs found

    Role of Tumor Necrosis Factor-╬▒ in the Human Systemic Endotoxin-Induced Transcriptome

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    <div><p>TNF╬▒ has been implicated in the pathogenesis of various inflammatory diseases. Different strategies to inhibit TNF╬▒ in patients with sepsis and chronic inflammatory conditions have shown contrasting outcomes. Although TNF╬▒ inhibitors are widely used in clinical practice, the impact of TNF╬▒ antagonism on white blood cell gene expression profiles during acute inflammation in humans <i>in vivo</i> has not been assessed. We here leveraged the established model of human endotoxemia to examine the effect of the TNF╬▒ antagonist, etanercept, on the genome-wide transcriptional responses in circulating leukocytes induced by intravenous LPS administration in male subjects. Etanercept pre-treatment resulted in a markedly dampened transcriptional response to LPS. Gene co-expression network analysis revealed this LPS-induced transcriptome can be categorized as TNF╬▒ responsive and non-responsive modules. Highly significant TNF╬▒ responsive modules include NF-kB signaling, antiviral responses and T-cell mediated responses. Within these TNF╬▒ responsive modules we delineate fundamental genes involved in epigenetic modifications, transcriptional initiation and elongation. Thus, we provide comprehensive information about molecular pathways that might be targeted by therapeutic interventions that seek to inhibit TNF╬▒ activity during human inflammatory diseases.</p></div

    TNF╬▒ responsive module hub (driver) genes and co-expression network visualization.

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    <p>Genes within transcriptional modules can be categorized as peripheral or hubs on the basis of how correlated a gene is with all other genes in the network, defined as the genes' connectivity measure, <b>k</b>. High intramodulr connectivities denote highly important module genes oftentimes possessing transcriptional factor activity. <b>A</b>. Unsupervised hierarchical clustering heatmap plot of the TNFα responsive module hub genes. Red denotes high expression; blue denotes low expression. The relative importance of each module within the co-expression network can be highlighted by unsupervised visualizations of each genes' weighted correlation coefficient. This was implemented in the Cytoscape® platform <b>B</b>. TNFα responsive co-expression modules were visualized by an organic layout considering weighted correlation coefficients >0.1 (equivalent to correlation coefficient >0.9).</p

    Genomic analysis of the systemic LPS-induced transcriptional response and impact of TNF╬▒ inhibition.

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    <p><b>A</b>. Volcano plot analysis (integrating p-values and log2 foldchanges) for the LPS-induced response in subjects treated with placebo. <b>B</b>. Volcano plot analysis of the LPS-induced response in subjects treated with the TNF╬▒ antagonist etanercept. Red dots in panels A and B indicate probes that showed a fold-change Ôëą1.5 or ÔëĄ1.5. <b>C</b>. Unsupervised hierarchical clustering heatmap of the 4077 LPS-induced transcripts that were influenced by etanercept treatment as identified by ANOVA (q-value <0.05). Columns represent subject samples and rows represent transcripts. Red indicates increased gene expression, and blue indicates decreased gene expression.</p

    LPS-induced TNF╬▒ responsive module genes linked to transcriptional initiation, elongation and epigenetic regulation.

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    <p>Genes within LPS-induced TNF╬▒ responsive co-expression modules possessing epigenetic regulation, transcriptional initiation and elongation properties. kTotal, total connectivity, k. kWithin, intra-modular connectivity. kOut, extra-modular connectivity. <i>log2</i> FC LPS, log2 transformed foldchange for the placebo-treated pre- and post-LPS challenged samples. <i>log2</i> FC LPS+Etan, log2 transformed foldchange for the etanercept-treated pre- and post-LPS challenged samples. Gene names marked in bold type denote module genes identified as top module hub genes.</p

    Functional annotation and hub genes for the LPS-induced co-expression modules.

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    <p>LPS-induced transcriptome is organized into 38 co-expression network modules. Each module was analyzed for enrichment of biological pathways by IPA (Ingenuity® systems, <a href="http://www.ingenuity.com" target="_blank">www.ingenuity.com</a>).</p