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

Autor: Edo Vellenga, Gwenny M. Fuhler, Karen A. Cadwallader, A. Lyndsay Drayer, Gerlinde J. Knol, Edwin R. Chilvers
Přispěvatelé: Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL)
Jazyk: angličtina
Rok vydání: 2004
Předmět:
phosphatidylinositol 3-kinase
Neutrophils
Immunology
Priming (immunology)
SIGNAL-TRANSDUCTION
TYROSINE KINASE
Granulocyte
Neutrophil Activation
Proinflammatory cytokine
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Phosphatidylinositol Phosphates
medicine
MDS
NADPH OXIDASE
Humans
Immunology and Allergy
RESPIRATORY BURST
Phosphatidylinositol
Enzyme Inhibitors
PRIMES
IN-VIVO
NADPH oxidase
biology
Phosphatidylinositol (3
4
5)-trisphosphate
Granulocyte-Macrophage Colony-Stimulating Factor
Chemotaxis
GM-CSF
Cell Biology
GAMMA
rac GTP-Binding Proteins
Respiratory burst
Enzyme Activation
N-Formylmethionine Leucyl-Phenylalanine
medicine.anatomical_structure
chemistry
PHOSPHOINOSITIDE 3-KINASES
Myelodysplastic Syndromes
CLASS IA
ras Proteins
biology.protein
ral GTP-Binding Proteins
Reactive Oxygen Species
cellular activation
signal transduction
Zdroj: Journal of Leukocyte Biology, 76(1), 254-262. FEDERATION AMER SOC EXP BIOL
ISSN: 0741-5400
DOI: 10.1189/jlb.0204071
Popis: 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.
Databáze: OpenAIRE
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