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Sotoodehnejadnematalahi, F.* ; Staples, K.J.* ; Chrysanthou, E.* ; Pearson, H.* ; Ziegler-Heitbrock, L. ; Burke, B.*

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

PLoS ONE 10:e0125799 (2015)
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Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Inducible Factor-i; Monocyte-derived Macrophages; Transcriptional Response; Differential Expression; Rheumatoid-arthritis; Flow-cytometry; Messenger-rna; Wound Repair; Blood-flow; Cells
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 10, Issue: 6, Pages: , Article Number: e0125799 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed