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 ac tions are not fully understood. Because of the roles of G-CSF and gelatinas e B in leucokinetics, we set out to characterize the interaction of G-CSF w ith its receptor in humans and its effects on gelatinase B release. G-CSF w as infused at bolus doses of 1 mug/kg and 5 mug/kg, and compared to placebo and dexamethasone (1 mg/kg b.i.d), which enhances the plasma levels of end ogenous 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 (CD1 14) on neutrophils by 75%. The G-CSF/CD114 interaction dose-independently i nduced 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 subs equent neutrophilia in animals. In this study. it was shown that G-CSF down modulates CD114 expression on the surface of neutrophils in humans and the consequent degranulation enhances gelatinase B release into plasma, which m ay contribute to mobilization of neutrophils or stem cells.