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 Fe(2+)
ions. Although
hypoxia inducible factor-1alpha (HIF-1alpha)
mRNA was identified in freshly isolated neutrophils, HIF-1alpha
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-1alpha 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.