uPA/uPAR System Is Active in Immature Dendritic Cells Derived from CD14+CD34+ Precursors and Is Down-Regulated upon Maturation

Ferrero, Elisabetta; Vettoretto, Katuscia; Bondanza, Attilio; Villa, Antonello; Resnati, Massimo; Poggi, Alessandro; Zocchi, Maria Raffaella

doi:10.4049/jimmunol.164.2.712

Cited by 33 publications

(24 citation statements)

References 45 publications

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“…The cell type where these pathways are activated may have different biological outcomes such as migration and motility, growth and differentiation, etc. (Yebra et al, 1996;Stepanova et al, 1997;Dumler et al, 1999;Ferrero et al, 2000). As the binding of uPA to uPAR is critical for the activation of Erk, we can hypothesise that high level of endogenous uPA expressed and secreted by WT and mock-transfected HCT116 cells can bind to excess uPAR on the cell surface, and thereby regulate the steady-state level of active Erk.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR–β1 integrin complex in colon cancer cells

et al. 2003

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Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and b1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/b1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with b1 integrin in mock-transfected cells. Disruption of uPAR -b1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR -integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.

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Section: Discussionmentioning

confidence: 99%

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR–β1 integrin complex in colon cancer cells

et al. 2003

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“…Thus, DA-3/sec cells most likely recruit less MDSCs due to their down-regulation of uPA. It has previously been shown that uPA is critical for macrophage chemotaxis, 38 basophil chemotaxis, 39 migration, and invasion of immature DCs, 40 and uPA Ϫ/Ϫ mice fail to recruit inflammatory cells to sites of infections. 41 Furthermore, it has been shown in human neutrophils that uPA can form a trimolecular complex with its receptor, uPAR, and the CD11b integrin, resulting in enhanced adhesion and migration.…”

Section: Discussionmentioning

confidence: 99%

Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec

Ilkovitch¹,

López

2009

Blood

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IntroductionMucin 1 (MUC1) is a tumor antigen that is overexpressed on the surface of various epithelial tumor cells. The transmembrane isoform of MUC1 can promote tumor progression by creating a barrier around tumor cells against immune cells, sequestering compounds that suppress immune responses, interacting with growth-promoting signaling molecules, and aiding in the metastatic process. 1 Furthermore, MUC1 has been shown to accelerate premalignant inflammatory lesion transformation to malignancy. 2 We have previously reported on antitumor properties of a splice variant of MUC1, which is secreted and known as MUC1/sec. [3][4][5] MUC1/sec is found in normal 6,7 and tumor tissue, 8 but, interestingly, malignancy in ovarian lesions has been correlated with loss of its expression. 9 DA-3 murine mammary tumor cells expressing MUC1/sec (DA-3/sec) are rejected from BALB/c mice, whereas expression of the transmembrane isoform of MUC1 (MUC1/TM; DA-3/TM) has little effect. [3][4][5] DA-3/sec cells, however, lead to tumor development in immunocompromised BALB/c nude mice, or BALB/c mice depleted of T lymphocytes. Furthermore, depletion of innate immune cells allows initial tumor growth, followed by tumor regression once the adaptive immune response develops. 3 We have determined that MUC1/sec modulates various factors involved in tumorigenesis, such as up-regulating signal transducer and activator of transcription 1 (Stat1), leading to the downregulation of tumor-derived urokinase plasminogen activator (uPA), a serine protease correlated with tumor progression in human cancers. 5 Other investigators have reported that tumor cell expression of MUC1/TM recruits immature dendritic cells (DCs). 10 In our previous studies, we analyzed whether there was a difference in recruitment of immune cells to DA-3/TM or DA-3/sec cells, and we reported that DA-3/TM cells recruit more GR-1 ϩ cells than DA-3/sec tumor cells. 3 We and others have also previously described that a myeloid population that accumulates in many tumor models, and are known as CD11b ϩ GR-1 ϩ myeloid-derived suppressor cells (MDSCs), [11][12][13][14][15][16] orchestrate immunosuppression by suppressing T cells. 13 In this study, we show that GR-1 ϩ cells that are recruited to high levels by DA-3/TM cells, but not DA-3/sec, are in fact MDSCs. Furthermore, we report for the first time that uPA, which is down-regulated by MUC1/sec, is capable of recruiting MDSCs. This is a new mechanism by which uPA may be augmenting and contributing to tumor development.MUC1 has also been shown to impair differentiation and function of DCs, 17 along with inducing a regulatory phenotype with immune-suppressive cytokine secretion. 10,17,18 We therefore investigated whether in addition to modulating recruitment of MDSCs, MUC1/sec can alter MDSC-suppressive mechanisms. We found that whereas DA-3/TM cells induce high levels of arginase in MDSCs, associated with suppression, 19 DA-3/sec cells block that induction. Furthermore, a unique peptide found in MUC1/sec and called immunoenhancing pe...

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“…However, pro-uPA consistently inhibited virus production in a lymphoid organ-tissue culture system, in which T cells are mostly in a resting state (39) but are, nevertheless, permissive for both R5 and X4 HIV infection (40) without requiring in vitro activation (41,51).…”

Section: Discussionmentioning

confidence: 99%

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

Alfano

Sidénius

Panzeri

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Elevated levels of soluble urokinase-type plasminogen activator (uPA) receptor, CD87͞u-PAR, predict survival in individuals infected with HIV-1. Here, we report that pro-uPA (or uPA) inhibits HIV-1 expression in U937-derived chronically infected promonocytic U1 cells stimulated with phorbol 12-myristate 13-acetate (PMA) or tumor necrosis factor-␣ (TNF-␣). However, pro-uPA did not inhibit PMA or TNF-␣-dependent activation of nuclear factor-kB or activation protein-1 in U1 cells. Cell-associated HIV protein synthesis also was not decreased by pro-uPA, although the release of virion-associated reverse transcriptase activity was substantially inhibited, suggesting a functional analogy between pro-uPA and the antiviral effects of IFNs. Indeed, cell disruption reversed the inhibitory effect of pro-uPA on activated U1 cells, and ultrastructural analysis confirmed that virions were preferentially retained within cell vacuoles in pro-uPA treated cells. Neither expression of endogenous IFNs nor activation of the IFN-inducible Janus kinase͞ signal transducer and activator of transcription pathway were induced by pro-uPA. Pro-uPA also inhibited acute HIV replication in monocyte-derived macrophages and activated peripheral blood mononuclear cells, although with great inter-donor variability. However, pro-uPA inhibited HIV replication in acutely infected promonocytic U937 cells and in ex vivo cultures of lymphoid tissue infected in vitro. Because these effects occurred at concentrations substantially lower than those affecting thrombolysis, pro-uPA may represent a previously uncharacterized class of antiviral agents mimicking IFNs in their inhibitory effects on HIV expression and replication.

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uPA/uPAR System Is Active in Immature Dendritic Cells Derived from CD14+CD34+ Precursors and Is Down-Regulated upon Maturation

Cited by 33 publications

References 45 publications

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR–β1 integrin complex in colon cancer cells

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR–β1 integrin complex in colon cancer cells

Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec

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

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