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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24236088/?tool=EBI |
| _version_ | 1818338009345425408 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T15:04:18Z |
| format | Article |
| id | doaj.art-80163fdce7f3411da037a891373af1ab |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T15:04:18Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-80163fdce7f3411da037a891373af1ab2022-12-21T23:41:03ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7905110.1371/journal.pone.0079051Role of tumor necrosis factor-α in the human systemic endotoxin-induced transcriptome.Brendon P SciclunaCornelis van 't VeerMax NieuwdorpKaren FelsmannBritta WlotzkaErik S G StroesTom van der PollTNFα 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24236088/?tool=EBI |
| spellingShingle | 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. PLoS ONE |
| 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24236088/?tool=EBI |
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