title: Impaired interleukin-8- and GROalpha-induced phosphorylation of extracellular signal-regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia.
abstract: Patients with myelodysplasia suffer from recurrent bacterial infections as a result of differentiation defects of the myeloid lineage and a disturbed functioning of neutrophilic granulocytes. Important physiological activators of neutrophils are the cytokines interleukin-8/CXC chemokine ligand 8 (IL-8/CXCL8), which activates CXC chemokine receptor 1 and 2 (CXCR1 and CXCR2), and growth-related oncogene (GROalpha)/CXCL1, which stimulates only CXCR2. In this study, we show that migration toward IL-8/GROalpha gradients is decreased in myelodysplastic syndrome (MDS) neutrophils compared with healthy donors. We investigated the signal transduction pathways involved in IL-8/GROalpha-induced migration and showed that specific inhibitors for extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol-3 kinase (PI-3K) abrogated neutrophil migration toward IL-8/GROalpha. In accordance with these results, we subsequently showed that IL-8/GROalpha-stimulated activation of ERK1/2 was substantially diminished in MDS neutrophils. Activation of the PI-3K downstream target protein kinase B/Akt was disturbed in MDS neutrophils when cells were activated with IL-8 but normal upon GROalpha stimulation. IL-8 stimulation resulted in higher migratory behavior and ERK1/2 activation than GROalpha stimulation, suggesting a greater importance of CXCR1. We then investigated IL-8-induced activation of the small GTPase Rac implicated in ERK1/2-dependent migration and found that it was less efficient in neutrophils from MDS patients compared with healthy donors. In contrast, IL-8 triggered a normal activation of the GTPases Ras and Ral, indicating that the observed defects were not a result of a general disturbance in CXCR1/2 signaling. In conclusion, our results demonstrate a disturbed CXCR1- and CXCR2-induced neutrophil chemotaxis in MDS patients, which might be the consequence of decreased Rac-ERK1/2 and PI-3K activation within these cells.
authors.affiliation: Division of Hematology, Department of Medicine, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Gwenny M
authors.initials: GM
authors.lastname: Fuhler
authors.forename: Gerlinde J
authors.initials: GJ
authors.lastname: Knol
authors.forename: A Lyndsay
authors.initials: AL
authors.lastname: Drayer
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D016209:Interleukin-8 / Q000494:pharmacology*; D009190:Myelodysplastic Syndromes / Q000209:etiology*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins; D018631:ras Proteins