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Blood, 23 July 2009, Vol. 114, No. 4, pp. 844-859. Prepublished online as a Blood First Edition Paper on May 19, 2009; DOI 10.1182/blood-2008-12-195941. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-12-195941v1 114/4/844    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Fang, H.-Y. Articles by Lewis, C. E. PubMed PubMed Citation Articles by Fang, H.-Y. Articles by Lewis, C. E. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia Hsin-Yu Fang1, Russell Hughes1, Craig Murdoch2, Seth B. Coffelt1, Subhra K. Biswas3, Adrian L. Harris4, Randall S. Johnson5, Hongxia Z. Imityaz6, M. Celeste Simon6, Erik Fredlund7, Florian R. Greten8, Jordi Rius9, and Claire E. Lewis1 1 Academic Unit of Inflammation and Tumour Targeting and 2 Department of Oral and Maxillofacial Medicine & Surgery, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, United Kingdom; 3 Singapore Immunology Network, Biomedical Sciences Institutes, Agency for Science, Technology & Research (A*STAR), Singapore; 4 CRUK Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; 5 Molecular Biology Section, University of California, San Diego School of Medicine, La Jolla; 6 Abramson Family Cancer Research Institute, Philadelphia, PA; 7 Center for Molecular Pathology, Lund University, University Hospital MAS, Malmö, Sweden; 8 Second Department of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; and 9 Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla 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)-1β and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-B (NF-B) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1 and 2 or NF-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-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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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