Tomoko Betsuyaku, Fulu Liu, Robert M. Senior, Jeffery S. Haug, Eric J. Brown, Samuel L. Jones, Kouji Matsushima, Daniel C. Link
J Clin Invest.
1999;
103(6):825–832
doi:10.1172/JCI5191
This article Copyright © 1999, The American Society for Clinical Investigation
Abstract
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G
ranulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that is widely used to treat neutropenia. In addition to stimulating polymorphonuclear neutrophil (PMN) production, G-CSF may have significant effects 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 PMN function. Compared with wild-type PMNs, PMNs isolated from G-CSFR–deficient mice demonstrated markedly decreased chemotaxis to IL-8. PMN emigration into the skin of G-CSFR–deficient mice in response to IL-8 was also impaired. Significant chemotaxis defects were also seen in response to N-formyl-methionyl-leucyl-phenylalanine, zymosan-activated serum, or macrophage inflammatory protein-2. The defective chemotactic response to IL-8 does not appear to be due to impaired chemoattractant receptor function, as the number of IL-8 receptors and chemoattractant-induced calcium influx, actin polymerization, and release of gelatinase B were comparable to those of wild-type PMNs. Chemoattractant-induced adhesion of G-CSFR–deficient PMNs was significantly impaired, suggesting a defect in β2-integrin activation. Collectively, these data demonstrate that selective defects in PMN activation are present in G-CSFR–deficient mice and indicate that G-CSF plays an important role in regulating PMN chemokine responsiveness.
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