Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3

Blood. 2008 Sep 1;112(5):2046-54. doi: 10.1182/blood-2008-04-149575. Epub 2008 Jun 4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Biological Transport, Active / drug effects
  • Calcium Signaling / drug effects
  • Calpain / antagonists & inhibitors*
  • Caspase 3 / metabolism*
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • Neutrophils / cytology*
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Recombinant Proteins
  • bcl-2-Associated X Protein / metabolism

Substances

  • BAX protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Recombinant Proteins
  • bcl-2-Associated X Protein
  • Granulocyte Colony-Stimulating Factor
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Calpain
  • Caspase 3
  • Caspase 8
  • Caspase 9