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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827317/ https://www.ncbi.nlm.nih.gov/pubmed/24236088 http://dx.doi.org/10.1371/journal.pone.0079051 |
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author | Scicluna, Brendon P. van 't Veer, Cornelis Nieuwdorp, Max Felsmann, Karen Wlotzka, Britta Stroes, Erik S. G. van der Poll, Tom |
author_facet | Scicluna, Brendon P. van 't Veer, Cornelis Nieuwdorp, Max Felsmann, Karen Wlotzka, Britta Stroes, Erik S. G. van der Poll, Tom |
author_sort | Scicluna, Brendon P. |
collection | PubMed |
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 | Online Article Text |
id | pubmed-3827317 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38273172013-11-14 Role of Tumor Necrosis Factor-α in the Human Systemic Endotoxin-Induced Transcriptome Scicluna, Brendon P. van 't Veer, Cornelis Nieuwdorp, Max Felsmann, Karen Wlotzka, Britta Stroes, Erik S. G. van der Poll, Tom PLoS One Research Article 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. Public Library of Science 2013-11-13 /pmc/articles/PMC3827317/ /pubmed/24236088 http://dx.doi.org/10.1371/journal.pone.0079051 Text en © 2013 Scicluna et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Scicluna, Brendon P. van 't Veer, Cornelis Nieuwdorp, Max Felsmann, Karen Wlotzka, Britta Stroes, Erik S. G. van der Poll, Tom Role of Tumor Necrosis Factor-α in the Human Systemic Endotoxin-Induced Transcriptome |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827317/ https://www.ncbi.nlm.nih.gov/pubmed/24236088 http://dx.doi.org/10.1371/journal.pone.0079051 |
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