Trends in Immunology
Volume 25, Issue 8, 1 August 2004, Pages 450-455
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uPA and uPAR in fibrinolysis, immunity and pathology

https://doi.org/10.1016/j.it.2004.06.004Get rights and content

Abstract

The urokinase plasminogen activator (uPA) and its receptor (uPAR) exert pleiotropic functions over the course of both physiological and pathological processes. Data generated in deficient mice have underlined how uPA not only has a key role in fibrinolysis but also modulates the development of protective immunity. By contrast, uPAR anchors uPA at the cell surface and, in addition to favoring extracellular matrix degradation, regulates cell migration, cell adhesion and cell proliferation, thus influencing the development of inflammatory and immune responses. Here, we review the expression and function of uPA and uPAR, and correlate their role in fibrinolysis with immune, infectious and proliferative disorders. This Review is the second in a series on interactions between haemostasis and inflammation.

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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