title: Platelet factor 4/CXCL4 induces phagocytosis and the generation of reactive oxygen metabolites in mononuclear phagocytes independently of Gi protein activation or intracellular calcium transients.
abstract: Platelet factor 4 (PF-4), a platelet-derived CXC chemokine, is known to prevent human monocytes from apoptosis and to promote differentiation of these cells into HLA-DR(-) macrophages. In this study, we investigated the role of PF-4 in the control of acute monocyte proinflammatory responses involved in the direct combat of microbial invaders. We show that PF-4 increases monocyte phagocytosis and provokes a strong formation of oxygen radicals but lacks a chemotactic activity in these cells. Compared with FMLP, PF-4-induced oxidative burst was later in its onset but was remarkably longer in its duration (lasting for up to 60 min). Furthermore, in PF-4-prestimulated cells, FMLP- as well as RANTES-induced burst responses became synergistically enhanced. As we could show, PF-4-mediated oxidative burst in monocytes does not involve Gi proteins, elevation of intracellular free calcium concentrations, or binding to CXCR3B, a novel PF-4 receptor recently discovered on endothelial cells. Moreover, we found that PF-4 acts on macrophages in a dual manner. On the one hand, very similar to GM-CSF or M-CSF, PF-4 treatment of monocytes generates macrophages with a high capacity for unspecific phagocytosis. On the other hand, short term priming of GM-CSF-induced human macrophages with PF-4 substantially increases their capability for particle ingestion and oxidative burst. A comparable effect was also observed in murine bone marrow-derived macrophages, indicating cross-reactivity of human PF-4 between both species. Taken together, PF-4 may play a crucial role in the induction and maintenance of an unspecific immune response.
authors.affiliation: Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Pervushina
authors.forename: Barbara
authors.initials: B
authors.lastname: Scheuerer
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.forename: Lars
authors.initials: L
authors.lastname: Behnke
authors.forename: Jens-M
authors.initials: JM
authors.lastname: Schröder
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kasper
authors.forename: Ernst
authors.initials: E
authors.lastname: Brandt
authors.forename: Silvia
authors.initials: S
authors.lastname: Bulfone-Paus
authors.forename: Frank
authors.initials: F
authors.lastname: Petersen
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018946:Chemokine CCL5 / Q000494:pharmacology; D004357:Drug Synergism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects*; D010978:Platelet Factor 4 / Q000494:pharmacology* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects*; D013045:Species Specificity; D013268:Stimulation, Chemical
chemical_list: C515187:CXCR3 protein, human; D018946:Chemokine CCL5; C515188:Cxcr3 protein, mouse; D017382:Reactive Oxygen Species; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D010978:Platelet Factor 4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go