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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1602-1610.
Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-08-2802.
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CHEMOKINES
Platelet factor 4 (PF-4)–induced neutrophil adhesion is controlled by src-kinases, whereas PF-4–mediated exocytosis requires the additional activation of p38 MAP kinase and phosphatidylinositol 3-kinase
Brigitte Kasper,
Ernst Brandt,
Silvia Bulfone-Paus, and
Frank Petersen
From the Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany.
Among the various chemokines that are functionally active on neutrophils, platelet factor 4 (PF-4; CXCL4) appears to have a specialized role. Lacking typical chemokine activities, PF-4 stimulates neutrophils to undergo firm adhesion to endothelial cells and, in the presence of an appropriate costimulus like tumor necrosis factor (TNF), PF-4 induces exocytosis of secondary granule contents. Analyzing the individual contribution of PF-4 and its costimuli in the control of these functions at the signaling level, we demonstrate that TNF-induced activation of p38 mitogen-activated protein (MAP) kinase (but not extracellular regulated kinase [Erk] kinases) acts as general and essential costimulatory signal in PF-4–dependent neutrophil exocytosis. This was shown by the use of a specific inhibitor (SB203580), by biologic (lipopolysaccharide, N-formyl-methionyl-leucyl-phenylalanine) and pharmacologic (anisomycin) activators of p38 MAP kinase, and by phosphorylation studies. Furthermore, TNF-mediated activation of phosphatidylinositol 3-kinase (PI 3-kinase) represents an additional essential signaling component in this process as demonstrated by studies with its inhibitor wortmannin as well as by analysis of the phosphorylation of AKT kinase. PF-4, however, directly activates src-kinases and PF-4–induced adherence as well as PF-4/TNF-mediated exocytosis was inhibited by an src-kinase inhibitor PP1. Taken together, neutrophil exocytosis and adherence are regulated on p38 MAP kinase, PI 3-kinase, and src-kinase activation.
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