T. Betsuyaku et al., A functional granulocyte colony-stimulating factor receptor is required for normal chemoattractant-induced neutrophil activation, J CLIN INV, 103(6), 1999, pp. 825-832
Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth fac
tor that is widely used to treat neutropenia. In addition to stimulating po
lymorphonuclear neutrophil (PMN) production, G-CSF may have significant eff
ects on PMN function. Because G-CSF receptor (G-CSFR)-deficient mice do not
have the expected neutrophilia after administration of human interleukin-8
(IL-8), we examined the effect of the loss of G-CSFR on IL-8-stimulated PM
N function. Compared with wild-type PMNs, PMNs isolated from G-CSFR-deficie
nt mice demonstrated markedly decreased chemo taxis to IL-8. PMN emigration
into the skin of G-CSFR-deficient mice in response to IL-8 was also impair
ed. Significant chemotaxis defects were also seen in response to N-formyl-m
ethionyl-leucyl-phenylalanine, zymosan-activated serum, or macrophage infla
mmatory protein-2. The defective chemotactic response to IL-8 does not appe
ar to be due to impaired chemoattractant receptor function, as the number o
f IL-8 receptors and chemoattractant-induced calcium influx, actin polymeri
zation, and release of gelatinase B were comparable to those of wild-type P
MNs. Chemoattractant-induced adhesion of G-CSFR-deficient PMNs was signific
antly impaired, suggesting a defect in beta 2-integrin activation. Collecti
vely, these data demonstrate that selective defects in PMN activation are p
resent in G-CSFR-deficient mice and indicate that G-CSF plays an important
role in regulating PMN chemokine responsiveness.