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.
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.
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany.
Brigitte
B
Kasper
Ernst
E
Brandt
Silvia
S
Bulfone-Paus
Frank
F
Petersen
D000841:Anisomycin / Q000494:pharmacology; D015153:Blotting, Western; D002448:Cell Adhesion; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007781:Lactoferrin / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010978:Platelet Factor 4 / Q000378:metabolism / Q000502:physiology*; D011233:Precipitin Tests; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D010978:Platelet Factor 4; D000841:Anisomycin; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007781:Lactoferrin; C093642:SB 203580