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Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

Fang, Hsin-Yu; Hughes, Russell; Murdoch, Craig; Coffelt, Seth B.; Biswas, Subhra K.; Harris, Adrian L.; Johnson, Randall S.; Imityaz, Hongxia Z.; Simon, M. Celeste and Fredlund, Erik LU , et al. (2009) In Blood 114(4). p.844-859
Abstract
Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1 beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the... (More)
Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1 beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappa B (NF-kappa B) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1 alpha and 2 alpha or NF-kappa B in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappa B, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors. (Blood. 2009; 114: 844-859) (Less)
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publication status
published
subject
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Blood
volume
114
issue
4
pages
844 - 859
publisher
American Society of Hematology
external identifiers
  • wos:000268257400019
  • scopus:68249140395
ISSN
1528-0020
DOI
10.1182/blood-2008-12-195941
language
English
LU publication?
yes
id
5f5709be-4d4f-483e-94ca-4d13960100fd (old id 1461830)
date added to LUP
2009-08-31 10:51:34
date last changed
2017-10-01 03:58:51
@article{5f5709be-4d4f-483e-94ca-4d13960100fd,
  abstract     = {Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1 beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappa B (NF-kappa B) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1 alpha and 2 alpha or NF-kappa B in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappa B, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors. (Blood. 2009; 114: 844-859)},
  author       = {Fang, Hsin-Yu and Hughes, Russell and Murdoch, Craig and Coffelt, Seth B. and Biswas, Subhra K. and Harris, Adrian L. and Johnson, Randall S. and Imityaz, Hongxia Z. and Simon, M. Celeste and Fredlund, Erik and Greten, Florian R. and Rius, Jordi and Lewis, Claire E.},
  issn         = {1528-0020},
  language     = {eng},
  number       = {4},
  pages        = {844--859},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia},
  url          = {http://dx.doi.org/10.1182/blood-2008-12-195941},
  volume       = {114},
  year         = {2009},
}