Granulocyte/macrophage colony-stimulating factor causes a paradoxical increase in the BH3-only pro-apoptotic protein Bim in human neutrophils.
Neutrophil apoptosis is essential for the resolution of inflammation but is delayed by several inflammatory mediators. In such terminally differentiated cells it has been uncertain whether these agents can inhibit apoptosis through transcriptional regulation of anti-death (Bcl-X(L), Mcl-1, Bcl2A1) or BH3-only (Bim, Bid, Puma) Bcl2-family proteins. We report that granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α prevent the normal time-dependent loss of Mcl-1 and Bcl2A1 in neutrophils, and we demonstrate that they cause an NF-κB-dependent increase in Bcl-X(L) transcription/translation. We show that GM-CSF and TNF-α increase and/or maintain mRNA levels for the pro-apoptotic BH3-only protein Bid and that GM-CSF has a similar NF-κB-dependent effect on Bim transcription and BimEL expression. The in-vivo relevance of these findings was indicated by demonstrating that GM-CSF is the dominant neutrophil survival factor in lung lavage from patients with ventilator-associated pneumonia, confirming an increase in lung neutrophil Bim mRNA. Finally GM-CSF caused mitochondrial location of Bim and a switch in phenotype to a cell that displays accelerated caspase-9-dependent apoptosis. This study demonstrates the capacity of neutrophil survival agents to induce a paradoxical increase in the pro-apoptotic proteins Bid and Bim and suggests that this may function to facilitate rapid apoptosis at the termination of the inflammatory cycle.
Cowburn
Andrew S
AS
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. asc32@cam.ac.uk
Summers
Charlotte
C
Dunmore
Benjamin J
BJ
Farahi
Neda
N
Hayhoe
Richard P
RP
Print
Cristin G
CG
Cook
Simon J
SJ
Chilvers
Edwin R
ER
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011014:Pneumonia / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053453:Caspase 9