Published online before print March 23, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0105024v1 78/1/202    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schaffner, A. Articles by Schaer, D. J. Search for Related Content PubMed PubMed Citation Articles by Schaffner, A. Articles by Schaer, D. J.

(Journal of Leukocyte Biology. 2005;78:202-209.)
© 2005 by Society for Leukocyte Biology

Regulated expression of platelet factor 4 in human monocytes—role of PARs as a quantitatively important monocyte activation pathway

Research Unit Medizinische Klinik B, University of Zurich, Switzerland

¹ Correspondence: Medizinische Klinik B, Universitätsspital AW 9, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: klinsar{at}usz.unizh.ch

Human mononuclear phagocytes have recently been shown to express constitutively and even more so, upon stimulation with bacteria, fungi, lipopolysaccharide (LPS), zymosan, or thrombin platelet basic protein (PBP). This CXC chemokine as well as platelet factor 4 (PF4), which is located genomically at a short distance from the PBP, were previously considered to be specific markers for the megakaryocyte cell lineage. Both chemokines have signaling and antimicrobial activity. In the present studies, transcriptional and expressional regulation of PF4 and related chemokines was studied in human monocytes. As shown by quantitative mRNA analysis, Western blots, radioimmunoprecipitation of cell extracts, and immunofluorescence and quantitatively with enzyme-linked immunosorbent assay, human monocytes express PF4 in the same order of magnitude as the known, regulated CXC chemokine interleukin (IL)-8. Expression of PF4 is up-regulated at the mRNA and protein level by thrombin and mediated by proteinase-activated receptors (PARs), resulting in a 32- to 128-fold higher mRNA level and leading to an up-to-sixfold increase of the peptide concentration in monocyte culture supernatants. Thrombin and the synthetic ligand of PAR-1 and PAR-2, SFLLRN, also induced comparable increases in the levels of mRNA for PBP, IL-8, regulated on activation, normal T expressed and secreted (RANTES), monocyte chemoattractant protein-1, and macrophage-inflammatory protein-1 and increased synthesis of these chemokines as shown by immunofluorescence or a quantitative immunobead-based method. The induction of increased mRNA levels for all chemokines by SFLLRN was unsurpassed by LPS, zymosan, interferon- (IFN-), tumor necrosis factor (TNF-), and IL-1. Activation of monocytes through PARs represents an alternate activation mechanism, independent from IFN-, TNF-, or other signaling pathways.

Key Words: macrophages • thrombin • antimicrobial cationic peptides • ß-thromboglobulin • chemokines • receptors • proteinase-activated

This article has been cited by other articles:

				V. Shpacovitch, M. Feld, M. D. Hollenberg, T. A. Luger, and M. Steinhoff Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity J. Leukoc. Biol., June 1, 2008; 83(6): 1309 - 1322. [Abstract] [Full Text] [PDF]

				C. A. Schaer, F. Vallelian, A. Imhof, G. Schoedon, and D. J. Schaer Heme carrier protein (HCP-1) spatially interacts with the CD163 hemoglobin uptake pathway and is a target of inflammatory macrophage activation J. Leukoc. Biol., February 1, 2008; 83(2): 325 - 333. [Abstract] [Full Text] [PDF]

				J. Vandercappellen, S. Noppen, H. Verbeke, W. Put, R. Conings, M. Gouwy, E. Schutyser, P. Proost, R. Sciot, K. Geboes, et al. Stimulation of angiostatic platelet factor-4 variant (CXCL4L1/PF-4var) versus inhibition of angiogenic granulocyte chemotactic protein-2 (CXCL6/GCP-2) in normal and tumoral mesenchymal cells J. Leukoc. Biol., December 1, 2007; 82(6): 1519 - 1530. [Abstract] [Full Text] [PDF]

				L. Lasagni, R. Grepin, B. Mazzinghi, E. Lazzeri, C. Meini, C. Sagrinati, F. Liotta, F. Frosali, E. Ronconi, N. Alain-Courtois, et al. PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion Blood, May 15, 2007; 109(10): 4127 - 4134. [Abstract] [Full Text] [PDF]

				N. Lippuner, B. Morell, A. Schaffner, and D. J. Schaer Proteinase-activated receptors induce nonoxidative, antimicrobial peptides and increased antimicrobial activity in human mononuclear phagocytes J. Leukoc. Biol., February 1, 2007; 81(2): 465 - 473. [Abstract] [Full Text] [PDF]

				B. Piqueras, J. Connolly, H. Freitas, A. K. Palucka, and J. Banchereau Upon viral exposure, myeloid and plasmacytoid dendritic cells produce 3 waves of distinct chemokines to recruit immune effectors Blood, April 1, 2006; 107(7): 2613 - 2618. [Abstract] [Full Text] [PDF]