Requirement for receptor‐bound urokinase in plasmin‐dependent cellular conversion of latent TGF‐β to TGF‐β

Odekon, Lale; Blasi, Francesco; Rifkin, Daniel B.

doi:10.1002/jcp.1041580303

Cited by 168 publications

(92 citation statements)

References 45 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T cells produce TGF-␤ as a latent precursor that needs to be converted into a biologically active form (46,47,50). Activated T cells express the urokinase plasminogen activator receptor that converts latent to active TGF-␤1 and IL-2 up-regulates this activity (51,52). Thus, one function of IL-2 could be to support the constant source of active TGF-␤ that is needed to maintain Treg Foxp3 expression.…”

Section: Discussionmentioning

confidence: 99%

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

Zheng

Wang

et al. 2007

The Journal of Immunology

533

418

View full text Add to dashboard Cite

IL-2 and TGF-β both have important roles in the induction and maintenance of immunologic tolerance, but whether these cytokines act separately or together to achieve this effect is poorly understood. Although others have reported that IL-2 can directly enhance forkhead box protein P3 (Foxp3) transcription factor expression by natural CD4+CD25+ regulatory T cells, in this study, we report that the role of IL-2 on the generation of peripheral regulatory CD4+ cells is indirect. Ab neutralization studies and experiments with IL-2-deficient mice have revealed that IL-2 is required for TGF-β to induce naive CD4+CD25− cells to become CD25+ and express Foxp3, and develop the characteristic properties of CD4+CD25+ regulatory cells. This effect of IL-2 on the generation and expansion of these adaptive Foxp3+ regulatory cells is nonredundant, but IL-4, IL-7, and IL-15, other common γ-chain cytokines, could sustain Foxp3 expression. Because subjects with autoimmune diseases often have defects in the production of IL-2 and/or TGF-β, the generation of autologous T regulatory cells ex vivo with these cytokines for transfer in vivo may have considerable therapeutic potential.

show abstract

Section: Discussionmentioning

confidence: 99%

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

Zheng

Wang

et al. 2007

The Journal of Immunology

533

418

View full text Add to dashboard Cite

show abstract

“…Urokinase acts by degradation of pericellular matrix, because of proteolytic cascade focused on cell surface leading to plasmin generation and matrix metalloprotease activation (Andreasen et al, 1997) but also by an increased cell migration independent of proteolysis (Silvestri et al, 2002). In addition, in relation to plasmin formation, uPA activates latent growth factors and releases growth factors bound to extracellular matrix (Odekon et al, 1994;Ribatti et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Cooperation between monocytes and breast cancer cells promotes factors involved in cancer aggressiveness

Blot

Chen

Vasse³

et al. 2003

Br J Cancer

View full text Add to dashboard Cite

In breast cancers, clinical symptoms of inflammation localised around the tumour at the time of diagnosis have been considered to have poor prognosis significance. In this study, the biological mechanisms responsible for the deleterious action of monocytes in cancer were investigated. The incubation of the breast-cancer-derived MDA-MB231 cells with monocytes resulted in an increase in factors involved in cell invasion (i.e. both cancer cells and monocytes-associated urokinase and Tissue Factor, and PAI-1 and MMP-9 secretion). Moreover, the functions of monocytes were also modified. Incubation of monocytes with MDA-MB231 cancer cells resulted in a downregulation in the secretion of the antiproliferative cytokine Oncostatin M, while the apoptotic factor TNF alpha was dramatically increased. However, MDA-MB231 cancer cells have been shown to be resistant towards the apoptotic action of TNF alpha. These findings demonstrate that incubation of MDA-MB231 cancer cells with monocytes induced a crosstalk, which resulted in an increased expression of factors involved in cancer cell invasiveness and in a modification of monocytes function against cancer cells, while inflammatory effects were increased. British Journal of Cancer (2003) The importance of stroma in cancer formation, growth and dissemination is now well established. In order to generate an invasive tumour, cancer cells need several mutations, but also formally necessitate sustenance from noncancer stroma cells, which supply and permit cancer cell growth and invasion. The presence of cytokines and inflammatory cells in cancer stroma, indicating defence reaction against cancer, generally correspond to a poor prognosis (Kleer et al, 2000). Furthermore, in breast cancer, initial presentation with clinical symptoms of inflammation indicates a particular aggressiveness and a worst prognosis than other breast cancers (Chevallier, 1993;Palangie et al, 1994;Kleer et al, 2000). However, the mechanisms leading to the pathological action of stroma-localised inflammatory cells in cancer, such as monocytes, remain poorly understood.The current study was undertaken to explore whether the factors of aggressiveness expressed by cancer cells were modified in the presence of monocytes. We also analysed the consequences of the incubation of monocytes with MDA-MB231 cancer cells on functions of monocytes both in the defence against tumour cells and in inflammatory functions. For this purpose, we tested the consequences of the interaction of the highly invasive breastderived MDA-MB231 cancer cells with monocytes with an in vitro system. MATERIAL AND METHODS Monocytes isolationA measure of 80 mm of blood from healthy volunteers was collected in sterile polypropylene tubes (Costar, Cambridge, MA, USA) containing 7.5 ml of ACD (38 mM citric acid, 74 mM citrate and 136 mM glucose). Platelet-rich plasma was removed by centrifugation (10 min, 100 g at room temperature). Mononuclear cells were collected after centrifugation (45 min, 400 g at room temperature) in Leucosep tubes (Costar, C...

show abstract

“…Further studies are needed to reveal the specific mechanism by which plasmin suppresses macrophage accumulation in tumors, but two likely possibilities include the proteolytic activation of growth factors and the proteolytic modification of the extracellular matrix (Rifkin et al, 1999;Werb, 1997). Transforming growth factor-b1 is a powerful suppressor of inflammatory cell recruitment to tissues, and its proteolytic release from the latent transforming growth factor-b binding protein has been linked to plasmin (Kulkarni et al, 1993;Odekon et al, 1994;Sato et al, 1990;Shull et al, 1992). Many cell types, including monocytes/macrophages, have specific receptors for fibrin and fibrin degradation products, and plasmin-generated fibrin degradation products have been reported to have immunosuppressive properties (Plow and Edgington, 1986;Simon et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

et al. 2002

View full text Add to dashboard Cite

The specific functions of plasminogen, stromal plasminogen activator, stromal plasminogen activator receptor, and stromal plasminogen activator inhibitor in the progression of the murine soft tissue sarcoma, T241 were investigated. Negation of plasminogen to the tumor blunted the orthotopic growth of the sarcoma in syngeneic mice. The reduced tumor growth was associated with a dramatic increase in tumor-infiltrating F4/80-positive macrophages and a diminution of vessel density, but not with obvious differences in fibrin and collagen deposition, or invasiveness of the tumor. Ablation of plasminogen activation by the tumor stroma only modestly impaired the prolonged growth of the sarcoma, suggesting that tumor cell-produced plasminogen activator is sufficient to mediate productive plasminogen activation. Plasminogen facilitated sarcoma progression, angiogenesis, and suppression of macrophage infiltration in the absence of either stromal urokinase plasminogen activator receptor or stromal plasminogen activator inhibitor. These data demonstrate that tumor cell-produced plasminogen activator and host plasminogen cooperate to facilitate soft tissue sarcoma growth and suppress the accumulation of tumor-infiltrating macrophages.

show abstract

Requirement for receptor‐bound urokinase in plasmin‐dependent cellular conversion of latent TGF‐β to TGF‐β

Cited by 168 publications

References 45 publications

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

Cooperation between monocytes and breast cancer cells promotes factors involved in cancer aggressiveness

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

Contact Info

Product

Resources

About