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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3176-3178. Prepublished online as a Blood First Edition Paper on June 29, 2006; DOI 10.1182/blood-2006-04-018796. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-04-018796v1 108/9/3176    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Walmsley, S. R. Articles by Chilvers, E. R. Search for Related Content PubMed PubMed Citation Articles by Walmsley, S. R. Articles by Chilvers, E. R. Related Collections Apoptosis Clinical Trials and Observations Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES Brief report Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis Sarah R. Walmsley, Andrew S. Cowburn, Menna R. Clatworthy, Nicholas W. Morrell, Emma C. Roper, Vanessa Singleton, Patrick Maxwell, Moira K. B. Whyte, and Edwin R. Chilvers From the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom; Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, United Kingdom; and Department of Nephrology, Hammersmith Campus, Imperial College, London, United Kingdom. Neutrophils are key mediators of the innate immune response and are required to function at sites of low oxygenation. We have shown that in hypoxia neutrophils are protected from apoptosis via a mechanism dependent on prolyl hydroxylase domain/hypoxia-inducible factor 1 (PHD/HIF-1). This response would be predicted to involve the von Hippel Lindau protein (pVHL)–dependent ubiquitination and degradation of HIF-1. Patients with VHL disease inherit a mutation in one VHL allele, which allows us to study the effects of heterozygous VHL expression in human neutrophils. Neutrophils exhibited a striking "partial hypoxic" pheno-type, with delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions and preserved responses to low levels of oxygen. This provides direct evidence that the HIF-1/VHL pathway regulates the innate immune response in humans. It also establishes that heterozygous VHL defects are sufficient to perturb normal responses and illustrates the potential to use this to address the role of HIF and VHL in human biology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. R. Walmsley, N. N. McGovern, M. K. B. Whyte, and E. R. Chilvers The HIF/VHL Pathway: From Oxygen Sensing to Innate Immunity Am. J. Respir. Cell Mol. Biol., March 1, 2008; 38(3): 251 - 255. [Abstract] [Full Text] [PDF] M. C. M. Vissers and R. P. Wilkie Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1{alpha} J. Leukoc. Biol., May 1, 2007; 81(5): 1236 - 1244. [Abstract] [Full Text] [PDF]

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