Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3.
Neutrophils have a very short life span and undergo apoptosis within 24 hours after leaving the bone marrow. Granulocyte colony-stimulating factor (G-CSF) is essential for the recruitment of fresh neutrophils from the bone marrow but also delays apoptosis of mature neutrophils. To determine the mechanism by which G-CSF inhibits neutrophil apoptosis, the kinetics of neutrophil apoptosis during 24 hours in the absence or presence of G-CSF were analyzed in vitro. G-CSF delayed neutrophil apoptosis for approximately 12 hours and inhibited caspase-9 and -3 activation, but had virtually no effect on caspase-8 and little effect on the release of proapoptotic proteins from the mitochondria. However, G-CSF strongly inhibited the activation of calcium-dependent cysteine proteases calpains, upstream of caspase-3, via apparent control of Ca(2+)-influx. Calpain inhibition resulted in the stabilization of the X-linked inhibitor of apoptosis (XIAP) and hence inhibited caspase-9 and -3 in human neutrophils. Thus, neutrophil apoptosis is controlled by G-CSF after initial activation of caspase-8 and mitochondrial permeabilization by the control of postmitochondrial calpain activity.
Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research and Phagocytes, Amsterdam, The Netherlands. b.j.vanraam@gmail.com
Bram J
BJ
van Raam
Agata
A
Drewniak
Vincent
V
Groenewold
Timo K
TK
van den Berg
Taco W
TW
Kuijpers
D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors*; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D016179:Granulocyte Colony-Stimulating Factor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D002154:Calpain; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9