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Beta2-integrins and acquired glycoprotein IIb/IIIa (GPIIb/IIIa) receptors cooperate in NF-kappaB activation of human neutrophils

Item Type:Article
Title:Beta2-integrins and acquired glycoprotein IIb/IIIa (GPIIb/IIIa) receptors cooperate in NF-kappaB activation of human neutrophils
Creators Name:Salanova, B. and Choi, M. and Rolle, S. and Wellner, M. and Luft, F.C. and Kettritz, R.
Abstract:Microparticles from various cells are generated during inflammation. Platelet-derived microparticles (PMPs) harbor receptors that are not genuinely expressed by neutrophils. We tested whether or not functional GPIIb/IIIa receptors can be acquired by neutrophils via PMPs and whether these receptors participate in pro-inflammatory signaling. Surface expression was analyzed by flow cytometry and confocal microscopy. NF-kappaB activation was analyzed by western blot experiments, electrophoretic mobility shift assays, and RT-PCR. Cell adhesion and spreading was estimated by myeloperoxidase assay and light microscopy. We found that PMPs transfer GPIIb/IIIa receptors to isolated and whole blood neutrophils via PMPs. We used specific antibodies in GM-CSF-treated neutrophils and observed that acquired GPIIb/IIIa receptors co-localized with beta2-integrins and cooperated in NF-kappaB activation. We show that Src and Syk non-receptor tyrosine kinases, as well as the actin cytoskeleton, control NF-kappaB activation. In contrast to NF-kappaB, acquisition of GPIIb/IIIa receptors was not necessary to induce adhesion to fibronectin or PI3K/Akt signaling. When GM-CSF-stimulated neutrophils were incubated on fibronectin, strong NF-kappaB activation was observed, but only after loading with PMPs. Blocking either beta2-integrins or GPIIb/IIIa receptors abrogated this effect. Therapeutic GPIIb/IIIa inhibitors were similarly effective. The compounds also inhibited NF-kappaB-dependent TNF-alpha mRNA up-regulation. The data implicate GPIIb/IIIa receptors as new therapeutic targets in neutrophil-induced inflammation.
Keywords:Blood Platelets, CD18 Antigens, Granulocyte-Macrophage Colony-Stimulating Factor, Immunoglobulin Fab Fragments, Integrin beta3, Monoclonal Antibodies, Neutrophils, NF-kappa B, Peptides, Phosphatidylinositol 3-Kinases, Platelet Aggregation Inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Membrane Glycoprotein IIb, Tumor Necrosis Factor-alpha, Tyrosine
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:282
Number:38
Page Range:27960-27969
Date:21 September 2007
Official Publication:https://doi.org/10.1074/jbc.M704039200
PubMed:View item in PubMed

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