Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis.
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.
D053607:Adrenomedullin; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D003676:Deferoxamine / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000097:blood / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D017931:DNA Primers; D016209:Interleukin-8; D007502:Iron Chelating Agents; D010455:Peptides; D011725:Pyridines; D012333:RNA, Messenger; C014047:hydroxypyridines; D053607:Adrenomedullin; D005947:Glucose; D003676:Deferoxamine