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Published online before print April 23, 2004

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(Journal of Leukocyte Biology. 2004;76:254-262.)
© 2004 by Society for Leukocyte Biology

Disturbed granulocyte macrophage-colony stimulating factor priming of phosphatidylinositol 3,4,5-trisphosphate accumulation and Rac activation in fMLP-stimulated neutrophils from patients with myelodysplasia

Gwenny M. Fuhler^*, Karen A. Cadwallader, Gerlinde J. Knol^*, Edwin R. Chilvers, A. Lyndsay Drayer and Edo Vellenga^*,1

^* Division of Hematology, Department of Medicine, University Hospital Groningen, The Netherlands;
Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, United Kingdom; and
Sanquin Blood Bank North East Netherlands, Groningen, The Netherlands

¹Correspondence: University Hospital Groningen, Department of Hematology Research, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: E.Vellenga{at}int.azg.nl

The production of reactive oxygen species (ROS) by human neutrophils is imperative for their bactericidal activity. Proinflammatory agents such as granulocyte macrophage-colony stimulating factor (GM-CSF) can prime ROS production in response to chemoattractants such as N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). In neutrophils from patients suffering from Myelodysplastic syndromes (MDS), a clonal, hematological disorder characterized by recurrent bacterial infections, this GM-CSF priming is severely impaired. In this study, we set out to further delineate the defects in neutrophils from MDS patients. We examined the effect of GM-CSF priming on fMLP-triggered activation of Rac, a small GTPase implicated in neutrophil ROS production. In contrast to healthy neutrophils, activation of Rac in response to fMLP was not enhanced by GM-CSF pretreatment in MDS neutrophils. Furthermore, activation of Rac was attenuated by pretreatment of neutrophils with the phosphatidylinositol 3-kinase (PI-3K) inhibitor LY294002. Unlike healthy neutrophils, fMLP-induced accumulation of the PI-3K lipid product PI(3,4,5)trisphosphate was not increased by GM-CSF pretreatment in MDS neutrophils. The disturbed Rac and PI-3K activation observed in MDS neutrophils did not appear to reflect a general GM-CSF or fMLP receptor-signaling defect, as fMLP-triggered Ras activation could be primed by GM-CSF in MDS and healthy neutrophils. Moreover, fMLP-induced activation of the GTPase Ral was also normal in neutrophils from MDS patients. Taken together, our data suggest that in neutrophils from MDS patients, a defect in priming of the PI-3K–Rac signaling pathway, located at the level of PI-3K, results in a decreased GM-CSF priming of ROS production.

Key Words: MDS • signal transduction • cellular activation • phosphatidylinositol 3-kinase

This article has been cited by other articles:

				G. M. Fuhler, N. R. Blom, P. J. Coffer, A. L. Drayer, and E. Vellenga The reduced GM-CSF priming of ROS production in granulocytes from patients with myelodysplasia is associated with an impaired lipid raft formation J. Leukoc. Biol., February 1, 2007; 81(2): 449 - 457. [Abstract] [Full Text] [PDF]

				G. M. Fuhler, G. J. Knol, A. L. Drayer, and E. Vellenga Impaired interleukin-8- and GRO{alpha}-induced phosphorylation of extracellular signal-regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia J. Leukoc. Biol., February 1, 2005; 77(2): 257 - 266. [Abstract] [Full Text] [PDF]