Trends in Immunology
uPA and uPAR in fibrinolysis, immunity and pathology
Section snippets
Structure and function
uPA is a serine protease that catalyzes the conversion of plasminogen to plasmin. Two crucial regions have been defined: the N-terminal domain, known as N-terminal fragment (ATF), which binds the receptor; and the C-terminal domain, which is endowed with catalytic activity. Binding to uPAR focuses proteolysis to the cell surface and serves to inactivate the enzyme when complexed with soluble inhibitors, such as plasminogen activator inhibitor 1 (PAI-1).
uPAR is a glycosylphosphatydilinositol
uPA, uPAR and fibrinolysis
uPA is considered to be one of the earliest mediators of fibrinolysis. It activates plasminogen into plasmin, which in turn degrades fibrin and prevents its extracellular deposition. This process might be dysregulated in several diseases involving inflammation and tissue repair. In animal models of septic shock [6], lung injury [7], impaired wound healing [8] and glomerulonephritis [9], reduced uPA-mediated proteolysis correlated with excessive fibrin deposition. Similarly, in a model of
uPA and uPAR in innate and adaptive immunity
The observation that both uPA and uPAR are expressed by a variety of cells of hemopoietic origin [19], and that the levels of various components of the PA system are upregulated during severe infections, supports a role for this system in the development of both innate and adaptive immune-mediated responses [20]. Indeed, circulating levels of uPA and its inhibitor PAI-1 are found following bacterial infection. This is caused by the ability of bacterial products, such as endotoxin, and of
uPA and uPAR in infectious and proliferative disorders
Recent data have revealed the increased expression of uPA and uPAR in the tissues or fluids of patients affected by AIDS and cancer. UPA was originally found to be involved in HIV infection because of its ability to cleave the gp120 envelope protein [42]. More recently, uPA, inactive pro-uPA or ATF have been demonstrated to exert a negative regulatory effect on both acutely and chronically HIV-infected cells [43]. In the case of uPAR, even though direct evidence for the functional implication
uPA and uPAR at the intersection between fibrinolysis, immunity and pathology
Together, the available data indicate that, in addition to fibrinolysis, the uPA–uPAR system might modulate several steps of the inflammatory cascade (Figure 2). In peripheral tissues, uPA–uPAR normally participates in physiological tissue remodeling events, as well as in local inflammatory manifestations. In the case of infection, or abnormal regulation of the PA cascade, uPA–uPAR might first favor the recruitment and activation of cells belonging to the innate immune response, as well as
Acknowledgements
We are grateful to all members of our laboratories for their helpful discussion and to the Associazione Italiana Ricerche sul Cancro (AIRC) for its continuous support.
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