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Mechanisms of hypoxic up-regulation of versican gene expression in macrophages

Mechanisms of hypoxic up-regulation of versican gene expression in macrophages
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. 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.
1932-6203
1-19
Sotoodehnejadnematalahi, Fattah
5913f7a4-4490-43a1-9829-58364cfcd958
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Chrysanthou, Elvina
ecc56956-2da2-400b-87a8-8c8566bdc53b
Pearson, Helen
5949c937-ba10-4ff2-9f15-8c60c7b7460f
Ziegler-Heitbrock, Loems
71bb9dd4-262c-46ba-9c10-1be5941ffca4
Burke, Bernard
cff79772-daee-4227-9002-3ad729923d17
Sotoodehnejadnematalahi, Fattah
5913f7a4-4490-43a1-9829-58364cfcd958
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Chrysanthou, Elvina
ecc56956-2da2-400b-87a8-8c8566bdc53b
Pearson, Helen
5949c937-ba10-4ff2-9f15-8c60c7b7460f
Ziegler-Heitbrock, Loems
71bb9dd4-262c-46ba-9c10-1be5941ffca4
Burke, Bernard
cff79772-daee-4227-9002-3ad729923d17

Sotoodehnejadnematalahi, Fattah, Staples, Karl J., Chrysanthou, Elvina, Pearson, Helen, Ziegler-Heitbrock, Loems and Burke, Bernard (2015) Mechanisms of hypoxic up-regulation of versican gene expression in macrophages. PLoS ONE, 10 (6), 1-19. (doi:10.1371/journal.pone.0125799). (PMID:26057378)

Record type: Article

Abstract

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.

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Accepted/In Press date: 26 March 2015
Published date: 9 June 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 378889
URI: https://eprints.soton.ac.uk/id/eprint/378889
ISSN: 1932-6203
PURE UUID: 2d3ee81d-cb02-464d-b35b-42d723a0a4f8
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 09 Jul 2015 09:32
Last modified: 06 Jun 2018 12:39

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Contributors

Author: Fattah Sotoodehnejadnematalahi
Author: Karl J. Staples ORCID iD
Author: Elvina Chrysanthou
Author: Helen Pearson
Author: Loems Ziegler-Heitbrock
Author: Bernard Burke

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