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.