Rapid down modulation of P-selectin glycoprotein ligand-1 (PSGL-1, CD162) by G-CSF in humans.
BACKGROUND
In vitro and animal studies suggest a critical role for P-selectin glycoprotein ligand-1 (PSGL-1) in the regulation of WBC adhesion and neutrophil counts. As WBC activation decreases PSGL-1 expression on WBCs in vitro, the effects of G-CSF on PSGL-1 expression were examined.


METHODS
Two different G-CSF doses (1 and 5 microg/kg IV) were compared with high-dose dexamethasone (1 mg/kg twice daily) and placebo in a randomized, double-blind, four-way cross-over trial in eight healthy volunteers. Surface expression of WBC adhesion molecules was quantified by flow cytometry.


RESULTS
Both G-CSF and dexamethasone led to a delayed down regulation of L-selectin. In contrast, G-CSF rapidly down regulated PSGL-1 expression on neutrophils within 90 minutes, whereas neither dexamethasone nor placebo had an effect. Similarly, incubation of WBCs with clinically relevant G-CSF concentrations (60 microg/L) for 90 minutes down modulated PSGL-1 expression on neutrophils and enhanced CD11b expression, compatible with a direct PSGL-1 down regulation by G-CSF-induced neutrophil activation. Similar to G-CSF, GM-CSF down regulated PSGL-1 in vitro. Both drugs induced shedding of soluble PSGL-1, supporting the concept that proteolytic cleavage is a potential mechanism of PSGL-1 down regulation on neutrophils.


CONCLUSIONS
G-CSF, but not dexamethasone, down regulates PSGL-1 expression on the surface of neutrophils in humans. This could also partly explain the synergistic effects when both drugs are combined for optimal mobilization of neutrophils for clinical granulocyte transfusion programs.
Jilma
Bernd
B
Department of Clinical Pharmacology-The Adhesion Research Group Elaborating Therapeutics, Vienna University School of Medicine, Vienna, Austria. bernd.jilma@univie.ac.at
Hergovich
Nicole
N
Homoncik
Monika
M
Marsik
Claudia
C
Kreuzer
Claudia
C
Jilma-Stohlawetz
Petra
P
D002462:Cell Membrane / Q000378:metabolism; D018592:Cross-Over Studies; D003907:Dexamethasone / Q000494:pharmacology; D004311:Double-Blind Method; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000648:ultrastructure; D005938:Glucocorticoids / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D019041:L-Selectin / Q000097:blood; D007958:Leukocyte Count; D008562:Membrane Glycoproteins / Q000097:blood*; D009504:Neutrophils / Q000378:metabolism; D010919:Placebos; D012995:Solubility; D020302:Weibel-Palade Bodies / Q000648:ultrastructure; D014841:von Willebrand Factor / Q000378:metabolism
D005938:Glucocorticoids; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D010919:Placebos; D014841:von Willebrand Factor; D019041:L-Selectin; D016179:Granulocyte Colony-Stimulating Factor; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor