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Impaired interleukin‐8‐ and GROα‐induced phosphorylation of extracellular signal‐regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia
Author(s) -
Fuhler Gwenny M.,
Knol Gerlinde J.,
Drayer A. Lyndsay,
Vellenga Edo
Publication year - 2005
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0504306
Subject(s) - cxc chemokine receptors , biology , signal transduction , chemokine , kinase , protein kinase b , mapk/erk pathway , cxcl1 , microbiology and biotechnology , stimulation , chemokine receptor , immunology , cancer research , endocrinology , immune system
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 (GROα)/CXCL1, which stimulates only CXCR2. In this study, we show that migration toward IL‐8/GROα gradients is decreased in myelodysplastic syndrome (MDS) neutrophils compared with healthy donors. We investigated the signal transduction pathways involved in IL‐8/GROα‐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/GROα. In accordance with these results, we subsequently showed that IL‐8/GROα‐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 GROα stimulation. IL‐8 stimulation resulted in higher migratory behavior and ERK1/2 activation than GROα 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.