Granulocyte Colony-Stimulating Factor (G-CSF) Downregulates Its Receptor (CD114) on Neutrophils and Induces Gelatinase B Release in Humans

Br J Haematol. 2000 Oct;111(1):314-20. doi: 10.1046/j.1365-2141.2000.02320.x.

Abstract

Despite the increasing use of granulocyte colony-stimulating factor (G-CSF) for the mobilization of stem cells and neutrophils, its pharmacodynamic actions are not fully understood. Because of the roles of G-CSF and gelatinase B in leucokinetics, we set out to characterize the interaction of G-CSF with its receptor in humans and its effects on gelatinase B release. G-CSF was infused at bolus doses of 1 microg/kg and 5 microg/kg, and compared to placebo and dexamethasone (1 mg/kg b.i.d), which enhances the plasma levels of endogenous G-CSF. The study was randomized, double-blind, four-way crossover, in eight healthy male volunteers. G-CSF dose-independently induced profound neutropenia (> 95%) within minutes and downregulated its own receptor (CD114) on neutrophils by 75%. The G-CSF/CD114 interaction dose-independently induced degranulation of neutrophils as evidenced by a 300-400% increase in CD11b expression. Degranulation induced up to a 10-fold increase in plasma levels of gelatinase B, an enzyme known to precipitate neutropenia and subsequent neutrophilia in animals. In this study, it was shown that G-CSF downmodulates CD114 expression on the surface of neutrophils in humans and the consequent degranulation enhances gelatinase B release into plasma, which may contribute to mobilization of neutrophils or stem cells.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens / analysis
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / blood*
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Prospective Studies
  • Protein Binding
  • Receptors, Granulocyte Colony-Stimulating Factor / metabolism*
  • von Willebrand Factor / immunology

Substances

  • Antigens
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Von Willebrand antigen
  • von Willebrand Factor
  • Granulocyte Colony-Stimulating Factor
  • Matrix Metalloproteinase 9