C. Grappone

Gabriella Fibbi; Marco Pucci; Silvia D'Alessio; C. Grappone; Giulia Pellegrini; Renata Salzano; Alessandro Casini; Stefano Milani; M. Del Rosso

The activation of hepatic stellate cells (HSC) during liver fibrogenesis has been shown to be mediated by paracrine and autocrine loops involving transforming growth factor-β1 (TGF-β1) as the main fibrogenic mediator secreted by activated macrophages, endothelial cells and liberated by disintegrated platelets. The cell-associated plasminogen activation system regulates extracellular matrix (ECM) catabolism and cell movement. We have studied whether TGF-β1 could modulate the plasminogen activation system in human HSC and the role of such protease system in the activity of TGF-β1 on HSC. Urokinase plasminogen activator receptors (u-PAR), u-PA and plasminogen activator inhibitor type 1 (PAI-1) were determined by immunoassay and RNase protection assay. Cell migration, evaluated either as chemotaxis or as chemoinvasion, was studied in Boyden chambers after addition of TGF-β1, and inhibition with anti-u-PA and anti-u-PAR antagonists [antibodies against u-PA and u-PAR and antisense oligonucleotides (aODN) against u-PAR mRNA]. We have shown that TGF-β1 is not mitogenic for HSC, while it is a powerful motogen either in chemotaxis or chemoinvasion assays. TGF-β1 up-regulates the synthesis and expression of PAI-1, as well as u-PAR expression and exposure at the cell membrane, while it does not affect u-PA levels. TGF-β1-dependent chemoinvasion of reconstituted basement membrane exploits the cell-associated plasminogen activation system, since it is blocked by monoclonal antibodies against u-PA and against various u-PAR domains, as well as by anti-u-PAR aODN. We have also observed a cumulative effect of TGF-β1, b-FGF and PDGF in the invasion assay of HSC: in the presence of low amounts of TGF-β1 the chemoinvasive activity of PDGF and bFGF is dramatically increased. Also this cooperation requires u-PAR and is inhibited by monoclonal antibodies against u-PAR domains I, II and III.

Massimo Pinzani; Stefano Milani; R De Franco; C. Grappone; Alessandra Caligiuri; A. Gentilini; C Tosti Guerra; Mario Maggi; Paola Failli; C. Ruocco; Paolo Gentilini

Fabio Marra; Raffaella DeFranco; C. Grappone; Stefano Milani; Sabrina Pastacaldi; Massimo Pinzani; Roberto Giulio Romanelli; Giacomo Laffi; Paolo Gentilini

Massimo Pinzani; Stefano Milani; Hermann Herbst; Raffaella DeFranco; C. Grappone; A. Gentilini; Alessandra Caligiuri; Giulia Pellegrini; Dac Vinh Ngo; Roberto Giulio Romanelli; Paolo Gentilini

Stefano Milani; Hermann Herbst; Detlef Schuppan; C. Grappone; Giulia Pellegrini; Massimo Pinzani; Alessandro Casini; Antonio Calabrò; G. Ciancio; Federico M. Stefanini

Fabio Marra; Raffaella DeFranco; C. Grappone; Maurizio Parola; Stefano Milani; Gabriella Leonarduzzi; Sabrina Pastacaldi; Ulrich Wenzel; Massimo Pinzani; Mario U. Dianzani; Giacomo Laffi; Paolo Gentilini

Tullio Barni; Guido Fantoni; Gloria L; Mario Maggi; Alessandro Peri; Balsi E; C. Grappone; Gabriella Barbara Vannelli

Del Rosso M; Gabriella Fibbi; Lucia Magnelli; Marco Pucci; Germana Dini; C. Grappone; Riccardo Caldini; Serni U; Colombo F; Borella F

Gabriella Fibbi; Lucia Magnelli; Germana Dini; Marco Pucci; C. Grappone; Riccardo Caldini; Marta Chevanne; Marco Del Rosso

M. Del Rosso; Gabriella Fibbi; Germana Dini; C. Grappone; Marco Pucci