The proteases, inhibitors, and receptors that comprise the plasminogen activator (PA)-plasmin fibrinolytic system are also integral to the pathogenesis of inflammatory tissue injury and repair. Recent evidence indicates that the uPA-CD87 system may actually be necessary for eliciting the optimal expression of some mononuclear phagocyte proinflammatory functions. Urokinase-type PA (uPA) bound to specific receptors (uPAR; CD87) on the mononuclear phagocyte plasma membrane appears to be important for the pericellular proteolysis necessary for penetrating tissue barriers, and CD87 is itself necessary for chemotaxin- driven locomotion. Mononuclear phagocyte-derived uPA activity can also influence the synthesis, release, and activation of cytokines, thereby regulating the availability of critical signals in the inflammatory milieu. The concept of introducing uPA or uPAR into """"""""mononuclear phagocyte activation"""""""" pathways is new, and little is presently known of the mechanisms by which these proteins operate. The central hypothesis underlying the proposed work is that uPA and CD87 are directly engaged in triggering many of the functional changes that comprise """"""""activated"""""""" phenotypes of mononuclear phagocytes. The long term goal of this project is to determine how uPA and CD87 regulate the engagement of mononuclear phagocyte in inflammatory responses. The short-term objectives are to i) determine whether signal transduction through CD87 directly initiates mononuclear phagocyte activation, and to determine whether blocking CD87 function modulates LPS-induced mononuclear phagocyte activation ii) characterize the differential effects on CD87 function exerted by the catalytic vs. ligand binding domains of uPA iii) determine the effects of PAI-1, a SERPIN-class PA inhibitor, on the functions of uPA and CD87 in mononuclear phagocyte activation iv) determine the effects of uPA and CD87 on the quantity, structure, and function of CR3, a beta2 integrin adhesion protein. Finally, studies will be performed to determine whether mononuclear phagocyte activation is optimized by a cooperative interaction between CD87 and CR3. uPA and CD87 are likely to exert potent regulatory effects on the ability of mononuclear phagocyte to mediate inflammation and subsequent repair. Hopefully, a more complete appreciation of the role of the uPA-CD87 system plays in mononuclear phagocyte activation will create new opportunities for favorably influencing mononuclear phagocyte functions in many conditions, including acute and chronic inflammation, wound healing, and atherogenesis.
