title: Haemostatic factors occupy new territory: the role of the urokinase receptor system and kininogen in inflammation.
abstract: Vascular cell adhesion and migration, proliferation or differentiation are cellular responses that are induced by haemostatic factors of the urokinase/plasminogen activation complex, but the respective underlying mechanisms are largely undefined. The direct and indirect contributions of the urokinase-type plasminogen activator receptor (uPAR) system in inflammatory processes, as they relate to recruitment of leukocytes, define novel functions and could serve as therapeutic targets for related vasculopathies. The presence of uPAR plays a crucial role in beta2-integrin-mediated adhesion of leukocytes; uPAR also directly mediates leukocyte adhesion to vitronectin, a multifunctional adhesion protein that is associated with the extracellular matrix. The latter process is inhibited by plasminogen activator inhibitor-1. Both beta2-integrin- and uPAR-dependent processes are activated by Zn2+ and are blocked by high-molecular-mass kininogen. Domain 5 of kininogen was identified, in particular, as an anti-adhesive component with a potent anti-inflammatory action in a peritonitis mouse model. In patients with acute myocardial infarction, elevated expression of uPAR on monocytes resulted in their increased adherence to the endothelium, which indicates a possible role of the uPAR system in monocyte recruitment to the infarcted area. Urokinase-type plasminogen activator was identified as a potent mitogen for vascular smooth muscle cells, an observation that was independent of the presence of uPAR and its proteolytic activity. Taken together, these results strongly suggest an essential role for the uPAR system in acute inflammation as well as in chronic degenerative vascular processes such as atherosclerosis. Targeting the uPAR system may allow specific therapeutic intervention in vascular pathologies.
authors.affiliation: Institut für Biochemie, Fachbereich Humanmedizin, Justus-Liebig-Universität, Friedrichstrasse 24, D-35392 Giessen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Chavakis
authors.forename: S M
authors.initials: SM
authors.lastname: Kanse
authors.forename: A E
authors.initials: AE
authors.lastname: May
authors.forename: K T
authors.initials: KT
authors.lastname: Preissner
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000209:etiology* / Q000473:pathology; D016023:Integrins / Q000502:physiology; D007704:Kininogens / Q000097:blood* / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D009203:Myocardial Infarction / Q000097:blood / Q000209:etiology / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology; D011956:Receptors, Cell Surface / Q000097:blood* / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
chemical_list: D016023:Integrins; D007704:Kininogens; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator