title: Platelet-derived MIF: a novel platelet chemokine with distinct recruitment properties.
abstract: OBJECTIVE
  Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with chemokine-like functions that plays a role in several inflammatory diseases including atherosclerosis. We recently demonstrated that in addition to macrophages and endothelial cells, platelets are a source of MIF. However, the functional relevance of platelet-derived MIF and differences to other platelet chemokines are unclear. Here, we sought to define the secretion pattern of platelet MIF and to characterize its functional profile in comparison with known atherogenic platelet chemokines.
  
  
  RESULTS
  Applying ELISA, we show that MIF is released from thrombin-stimulated platelets after 2 h, whereas CXCL12 and CXCL4 are secreted within minutes. Applied to platelets, MIF, unlike CXCL12, did not enhance platelet activation as analyzed by platelet aggregation, CD62P exposure and chemokine secretion studies. In contrast, both MIF and CXCL12 attenuated ADP-induced calcium transients in platelets. Transmigration and monocyte flow adhesion assays toward conditioned platelet supernatants together with MIF antibody blockade or supernatants from Mif(-/-) mice suggested that platelet-derived MIF has a stronger chemotactic activity than CXCL12 at its respective optimal secretion interval, and showed that platelet MIF substantially contributes to monocyte adhesion on endothelial layers. Moreover, MIF was found to delay clot retraction.
  
  
  CONCLUSIONS
  We demonstrate that MIF differs from other platelet-derived chemokines by delayed secretion kinetics and by a distinct autocrine/paracrine modulation potential. Importantly, MIF was found to be a major platelet-derived chemotactic recruitment factor with clot-modulating properties and therefore might be relevant in inflammatory diseases such as atherosclerosis.
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Theresa H
authors.initials: TH
authors.lastname: Wirtz
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tillmann
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strüßmann
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kraemer
authors.affiliation: Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.affiliation: Klinik für Anästhesiologie, RWTH Aachen University, Aachen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grottke
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Universität Tübingen, Tübingen, Germany.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: von Hundelshausen
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany; August-Lenz-Stiftung at Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: jbernhagen@ukaachen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000503:physiopathology; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D042783:Endothelial Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D008263:Macrophage Migration-Inhibitory Factors; D010978:Platelet Factor 4; D007770:L-Lactate Dehydrogenase; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse; D002118:Calcium
keywords: Atherogenesis; CXCL12; Chemokines; MIF; Monocytes; Platelets; Secretion