Altered levels of urokinase on monocytes and in serum of children with AIDS; effects on lymphocyte activation and surface marker expression

Abstract

Urokinase (UK) type plasminogen activator is a serine protease produced by activated human monocytes. Despite the well-documented roles played by UK in cell-mediated immunity in healthy humans, the roles played by UK in the derangements of cell-mediated immune responses observed in HIV disease remain largely undefined. In these studies the numbers of peripheral blood lymphocytes and monocytes bearing surface UK (UK ؉ ) as well as serum levels of UK (flow microfluorimetry and ELISA, respectively) were determined in children with AIDS and in healthy HIV-negative children. The effects of exogenous UK on lymphocyte activation (cell cycle analysis using living cells) and surface marker (CD3, CD4, CD8, and CD19) expression (flow microfluorimetry using fixed cells) were also studied. Data are expressed as percent total cells. Numbers of UK ؉ lymphocytes in children with AIDS were similar to those observed in healthy children. In contrast, numbers of UK ؉ peripheral blood monocytes were dramatically decreased (G70%) in the children with AIDS. However, serum levels of UK were increased (nearly threefold) in these children. When lymphocytes from these children were cultured with soluble UK, numbers of cells in S phase of cell cycle appeared suppressed. Incubation of fixed lymphocytes from either a child with AIDS or from a healthy child with exogenous UK appeared to increase numbers of cells expressing CD3. Incubation with UK had no effect on expression of any other surface marker (CD4, CD8, or CD19) using cells from the child with AIDS. In contrast, incubation with UK appeared to decrease (fivefold) numbers of cells expressing CD19 and increase numbers of cells expressing CD4 and CD8 only when fixed lymphocytes from a healthy HIV-negative child were used. The results suggest important roles for UK in regulation of lymphocyte surface markers in general and in CD3-and CD19-dependent lymphocyte activation pathways specifically. Furthermore, these studies add to a widening body of evidence implicating UK dysregulation in the pathogenesis of HIV disease and may point to pharmacological opportunities involving UK to delay or prevent progression of HIV infection into full-blown AIDS.

Plasma Concentrations of Soluble Urokinase‐Type Plasminogen Activator Receptor Are Increased in Patients with Malaria and Are Associated with a Poor Clinical or a Fatal Outcome

“…In healthy adults, the circulating concentration of suPAR is often between 1 and 2 ng/mL, depending on the sample material, the anticoagulant, and the assay used [27,52]. The reference concentration for suPAR in children is unknown, but the serum concentration of uPA is comparable in children and adults [53,54]. Although the median plasma concentration of suPAR was 12 ng/mL in the healthy children, such concentrations have previously been demonstrated in healthy adults [27].…”

Urokinase–urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication

“…On the other hand, uPA-uPAR has been shown to process CCL14 into an active form (54) and to modulate the chemotactic effect of CCL11 (55). In addition, uPA has been shown to increase the number of CD4 ϩ and CD8 ϩ T cells from healthy children in vitro (56), whereas uPA-deficient mice showed a reduced infiltration of CD4 ϩ ͞CD11b ϩ ͞CD18 ϩ cells in their lung and had an increased mortality by infection of Criptococcus neoformans (57). In vitro, HIV infection of cell lines, PBMC, and͞or MDM has resulted in increased expression of uPAR (13) as well as of certain CC chemokines such as CCL2 (58), CCL3, and CCL4 (59,60).…”

“…In this regard, we have recently shown that high serum levels of suPAR are a major negative prognostic factor in HIV infection independently of the clinical stage, viremia levels, and CD4 ϩ T cell counts (11). In addition, dysregulation of the uPA-uPAR system has been observed in children with AIDS in terms of a decreased number of uPA ϩ circulating monocytes (56) and, more recently, in granulocytes of HIV-infected individuals, where the levels of uPAR expression reflected the number of peripheral blood CD4 ϩ T lymphocytes (14).…”

Reduced Release of Intact and Cleaved Urokinase Receptor in Stimulated Whole‐Blood Cultures from Human Immunodeficiency Virus‐1‐Infected Patients

“…HIV‐1 infection is characterized by profound and inappropriate immune activation [22, 23], which may in part explain the perturbations in the uPA‐uPAR system associated with HIV‐1 infection. Thus, HIV‐1‐infected patients have high circulating levels of suPAR [1] and uPA [24], and the uPAR expression is reduced on granulocytes [25] but increased on activated T cells [4]. Furthermore, HIV‐1 infection of T and monocytic cell lines increases uPAR expression on both an mRNA and protein level [26, 27].…”