Granulocyte colony-stimulating factor (G-CSF) downregulates its receptor (CD114) on neutrophils and induces gelatinase B release in humans.
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.
Jilma
B
B
Department of Clinical Pharmacology-TARGET, Vienna University School of Medicine, Austria. bernd.jilma@univie.ac.at
Hergovich
N
N
Homoncik
M
M
Jilma-Stohlawetz
P
P
Kreuzer
C
C
Eichler
H G
HG
Zellner
M
M
Pugin
J
J
D000941:Antigens / Q000032:analysis; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011446:Prospective Studies; D011485:Protein Binding; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D014841:von Willebrand Factor / Q000276:immunology
D000941:Antigens; D016188:Receptors, Granulocyte Colony-Stimulating Factor; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; D016179:Granulocyte Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9