Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.

TNFα has been implicated in the pathogenesis of various inflammatory diseases. Different strategies to inhibit TNFα in patients with sepsis and chronic inflammatory conditions have shown contrasting outcomes. Although TNFα inhibitors are widely used in clinical practice, the impact of TNFα antagonis...

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Autores principales:	Brendon P Scicluna, Cornelis van 't Veer, Max Nieuwdorp, Karen Felsmann, Britta Wlotzka, Erik S G Stroes, Tom van der Poll
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/80163fdce7f3411da037a891373af1ab
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spelling	oai:doaj.org-article:80163fdce7f3411da037a891373af1ab2021-11-18T08:46:50ZRole of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.1932-620310.1371/journal.pone.0079051https://doaj.org/article/80163fdce7f3411da037a891373af1ab2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24236088/?tool=EBIhttps://doaj.org/toc/1932-6203TNFα has been implicated in the pathogenesis of various inflammatory diseases. Different strategies to inhibit TNFα in patients with sepsis and chronic inflammatory conditions have shown contrasting outcomes. Although TNFα inhibitors are widely used in clinical practice, the impact of TNFα antagonism on white blood cell gene expression profiles during acute inflammation in humans in vivo has not been assessed. We here leveraged the established model of human endotoxemia to examine the effect of the TNFα 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 TNFα responsive and non-responsive modules. Highly significant TNFα responsive modules include NF-kB signaling, antiviral responses and T-cell mediated responses. Within these TNFα 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 TNFα activity during human inflammatory diseases.Brendon P SciclunaCornelis van 't VeerMax NieuwdorpKaren FelsmannBritta WlotzkaErik S G StroesTom van der PollPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e79051 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Brendon P Scicluna Cornelis van 't Veer Max Nieuwdorp Karen Felsmann Britta Wlotzka Erik S G Stroes Tom van der Poll Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
description	TNFα has been implicated in the pathogenesis of various inflammatory diseases. Different strategies to inhibit TNFα in patients with sepsis and chronic inflammatory conditions have shown contrasting outcomes. Although TNFα inhibitors are widely used in clinical practice, the impact of TNFα antagonism on white blood cell gene expression profiles during acute inflammation in humans in vivo has not been assessed. We here leveraged the established model of human endotoxemia to examine the effect of the TNFα 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 TNFα responsive and non-responsive modules. Highly significant TNFα responsive modules include NF-kB signaling, antiviral responses and T-cell mediated responses. Within these TNFα 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 TNFα activity during human inflammatory diseases.
format	article
author	Brendon P Scicluna Cornelis van 't Veer Max Nieuwdorp Karen Felsmann Britta Wlotzka Erik S G Stroes Tom van der Poll
author_facet	Brendon P Scicluna Cornelis van 't Veer Max Nieuwdorp Karen Felsmann Britta Wlotzka Erik S G Stroes Tom van der Poll
author_sort	Brendon P Scicluna
title	Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
title_short	Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
title_full	Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
title_fullStr	Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
title_full_unstemmed	Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
title_sort	role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/80163fdce7f3411da037a891373af1ab
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Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.

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