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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0454.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 3008-3016
PHAGOCYTES
Involvement of a ferroprotein sensor in hypoxia-mediated
inhibition of neutrophil apoptosis
Katy I. Mecklenburgh,
Sarah
R. Walmsley,
Andrew S. Cowburn,
Michael Wiesener,
Benjamin J. Reed,
Paul D. Upton,
John Deighton,
Andrew P. Greening, and
Edwin R. Chilvers
From the Respiratory Medicine Division, Department of
Medicine, University of Cambridge School of Clinical Medicine,
Addenbrooke's and Papworth Hospitals, Cambridge; Respiratory Medicine
Unit, Department of Medicine, University of Edinburgh Medical School;
Respiratory Medicine Unit, Western General Hospital, Edinburgh; and
Institute of Molecular Medicine, John Radcliffe Hospital, Wellcome
Trust Centre for Human Genetics, Oxford, United Kingdom.
Neutrophil apoptosis represents a major mechanism involved in the
resolution of acute inflammation. In contrast to the effect of hypoxia
observed in many other cell types, oxygen deprivation, as we have
shown, causes a profound but reversible delay in the rate of
constitutive apoptosis in human neutrophils when aged in vitro. This
effect was mimicked by exposing cells to 2 structurally unrelated
iron-chelating agents, desferrioxamine (DFO) and
hydroxypyridines (CP-94), and it appeared specific for hypoxia
in that no modulation of apoptosis was observed with mitochondrial
electron transport inhibitors, glucose deprivation, or heat shock. The
involvement of chelatable iron in the oxygen-sensing mechanism was
confirmed by the abolition of the DFO and CP-94 survival effect by
Fe2+ ions. Although hypoxia inducible factor-1
(HIF-1) mRNA was identified in freshly isolated neutrophils,
HIF-1 protein was only detected in neutrophils incubated under
hypoxic conditions or in the presence of DFO. Moreover, studies with
cyclohexamide demonstrated that the survival effect of hypoxia was
fully dependent on continuing protein synthesis. These results indicate
that the neutrophil has a ferroprotein oxygen-sensing mechanism
identical to that for erythropoietin regulation and results in HIF-1
up-regulation and profound but reversible inhibition of neutrophil
apoptosis. This finding may have important implications for the
resolution of granulocytic inflammation at sites of low-oxygen tension.
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