Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity.
Neutrophils are key effector cells of the innate immune response and are required to migrate and function within adverse microenvironmental conditions. These inflammatory sites are characterized by low levels of oxygen and glucose and high levels of reductive metabolites. A major regulator of neutrophil functional longevity is the ability of these cells to undergo apoptosis. We examined the mechanism by which hypoxia causes an inhibition of neutrophil apoptosis in human and murine neutrophils. We show that neutrophils possess the hypoxia-inducible factor (HIF)-1alpha and factor inhibiting HIF (FIH) hydroxylase oxygen-sensing pathway and using HIF-1alpha-deficient myeloid cells demonstrate that HIF-1alpha is directly involved in regulating neutrophil survival in hypoxia. Gene array, TaqMan PCR, Western blotting, and oligonucleotide binding assays identify NF-kappaB as a novel hypoxia-regulated and HIF-dependent target, with inhibition of NF-kappaB by gliotoxin or parthenolide resulting in the abrogation of hypoxic survival. In addition, we identify macrophage inflammatory protein-1beta as a novel hypoxia-induced neutrophil survival factor.
Walmsley
Sarah R
SR
Division of Respiratory Medicine, Department of Medicine, School of Clinical Medicine, University of Cambridge, Addenbrooke's and Papworth Hospitals, Cambridge, CB2 2QQ, UK.
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Cristin
C
Farahi
Neda
N
Peyssonnaux
Carole
C
Johnson
Randall S
RS
Cramer
Thorsten
T
Sobolewski
Anastasia
A
Condliffe
Alison M
AM
Cowburn
Andrew S
AS
Johnson
Nicola
N
Chilvers
Edwin R
ER
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D054407:Chemokine CCL4; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005912:Gliotoxin; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases; D052002:NF-kappa B p50 Subunit; D009504:Neutrophils / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D012717:Sesquiterpenes; D014157:Transcription Factors / Q000378:metabolism*
D054407:Chemokine CCL4; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019402:Macrophage Inflammatory Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009687:Nuclear Proteins; D009841:Oligonucleotides; D012097:Repressor Proteins; D012717:Sesquiterpenes; D014157:Transcription Factors; C002669:parthenolide; D005912:Gliotoxin; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human