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J. Biol. Chem. 282 (38): 27960-27969

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

beta2-Integrins and Acquired Glycoprotein IIb/IIIa (GPIIb/IIIa) Receptors Cooperate in NF-{kappa}B Activation of Human Neutrophils*{diamondsuit}

Birgit Salanova, Mira Choi, Susanne Rolle, Maren Wellner, Friedrich C. Luft, , and Ralph Kettritz1

Franz Volhard Clinic and Max Delbrueck Center for Molecular Medicine, Medical Faculty of the Charité, HELIOS Kliniken, 13125 Berlin, Germany

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 glycoprotein IIb/IIIa (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-{kappa}B activation was analyzed by Western blot experiments, electrophoretic mobility shift assays, and reverse transcription-PCR. Cell adhesion and spreading were 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 granulocyte macrophage colony-stimulating factor-treated neutrophils and observed that acquired GPIIb/IIIa receptors co-localized with beta2-integrins and cooperated in NF-{kappa}B activation. We show that Src and Syk non-receptor tyrosine kinases, as well as the actin cytoskeleton, control NF-{kappa}B activation. In contrast to NF-{kappa}B, acquisition of GPIIb/IIIa receptors was not necessary to induce adhesion to fibronectin or phosphatidylinositol 3-kinase/Akt signaling. When granulocyte macrophage colony-stimulating factor-stimulated neutrophils were incubated on fibronectin, strong NF-{kappa}B 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-{kappa}B-dependent tumor necrosis factor-{alpha} mRNA up-regulation. The data implicate GPIIb/IIIa receptors as new therapeutic targets in neutrophil-induced inflammation.


Received for publication May 16, 2007. Revision received July 2, 2007.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{diamondsuit} This article was selected as a Paper of the Week.

1 To whom correspondence should be addressed: Division of Nephrology, Franz Volhard Clinic, Schwanebecker Chaussee 50, 13125 Berlin, Germany. Tel.: 49-30-940152801; Fax: 49-30-940152809; E-mail: kettritz{at}charite.de.


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