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

Bram J van Raam, Agata Drewniak, Vincent Groenewold, Timo K van den Berg, Taco W Kuijpers

Research output: Contribution to journalArticleAcademicpeer-review

108 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2046-54
Number of pages9
JournalBlood
Volume112
Issue number5
DOIs
Publication statusPublished - 1 Sept 2008

Keywords

  • 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
  • Models, Biological
  • Neutrophils/cytology
  • Recombinant Proteins
  • bcl-2-Associated X Protein/metabolism

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