Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.
During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.
Hollenstein
U
U
Department of Clinical Pharmacology, The Adhesion Research Group Elaborating Therapeutics, Vienna University Hospital School of Medicine, A-1090 Wien, Austria.
Homoncik
M
M
Stohlawetz
P J
PJ
Marsik
C
C
Sieder
A
A
Eichler
H G
HG
Jilma
B
B
D000328:Adult; D004311:Double-Blind Method; D015536:Down-Regulation; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*
D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor