Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.
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)-1beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappaB (NF-kappaB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1alpha and 2alpha or NF-kappaB 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-kappaB, 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.
Fang
Hsin-Yu
HY
Academic Unit of Inflammation and Tumour Targeting, Faculty of Medicine, Dentistry and Health,University of Sheffield, Beech Hill Road, Sheffield, United Kingdom.
Hughes
Russell
R
Murdoch
Craig
C
Coffelt
Seth B
SB
Biswas
Subhra K
SK
Harris
Adrian L
AL
Johnson
Randall S
RS
Imityaz
Hongxia Z
HZ
Simon
M Celeste
MC
Fredlund
Erik
E
Greten
Florian R
FR
Rius
Jordi
J
Lewis
Claire E
CE
D000818:Animals; D018929:Cell Culture Techniques; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C485502:HIF-2 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D014157:Transcription Factors