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Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages
Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Her...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461269/ https://www.ncbi.nlm.nih.gov/pubmed/26057378 http://dx.doi.org/10.1371/journal.pone.0125799 |
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author | Sotoodehnejadnematalahi, Fattah Staples, Karl J. Chrysanthou, Elvina Pearson, Helen Ziegler-Heitbrock, Loems Burke, Bernard |
author_facet | Sotoodehnejadnematalahi, Fattah Staples, Karl J. Chrysanthou, Elvina Pearson, Helen Ziegler-Heitbrock, Loems Burke, Bernard |
author_sort | Sotoodehnejadnematalahi, Fattah |
collection | PubMed |
description | Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression. |
format | Online Article Text |
id | pubmed-4461269 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44612692015-06-16 Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages Sotoodehnejadnematalahi, Fattah Staples, Karl J. Chrysanthou, Elvina Pearson, Helen Ziegler-Heitbrock, Loems Burke, Bernard PLoS One Research Article Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression. Public Library of Science 2015-06-09 /pmc/articles/PMC4461269/ /pubmed/26057378 http://dx.doi.org/10.1371/journal.pone.0125799 Text en © 2015 Sotoodehnejadnematalahi 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 Sotoodehnejadnematalahi, Fattah Staples, Karl J. Chrysanthou, Elvina Pearson, Helen Ziegler-Heitbrock, Loems Burke, Bernard Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages |
title | Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages |
title_full | Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages |
title_fullStr | Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages |
title_full_unstemmed | Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages |
title_short | Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages |
title_sort | mechanisms of hypoxic up-regulation of versican gene expression in macrophages |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461269/ https://www.ncbi.nlm.nih.gov/pubmed/26057378 http://dx.doi.org/10.1371/journal.pone.0125799 |
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