Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic system

G. Fibbi, M. Pucci, S. D'Alessio, C. Grappone, G. Pellegrini, R. Salzano, A. Casini, S. Milani, M. Del Rosso

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)87-100
Number of pages14
JournalGrowth Factors
Volume19
Issue number2
Publication statusPublished - 2001

Fingerprint

Urokinase Plasminogen Activator Receptors
Hepatic Stellate Cells
Transforming Growth Factors
Transforming Growth Factor beta
Plasminogen
Chemical activation
Assays
Plasminogen Activator Inhibitor 1
Chemotaxis
Cell Movement
Monoclonal Antibodies
Fibroblast Growth Factor 1
Antisense Oligonucleotides
Macrophages
Endothelial cells
Cell membranes
Ribonucleases
Platelets
Immunoassay
Basement Membrane

Keywords

  • Hepatic fibrosis
  • Hepatic stellate cells
  • Transforming growth factor-β1
  • Urokinase plasminogen activator receptors

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Endocrinology

Cite this

Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic system. / Fibbi, G.; Pucci, M.; D'Alessio, S.; Grappone, C.; Pellegrini, G.; Salzano, R.; Casini, A.; Milani, S.; Del Rosso, M.

In: Growth Factors, Vol. 19, No. 2, 2001, p. 87-100.

Research output: Contribution to journalArticle

Fibbi, G, Pucci, M, D'Alessio, S, Grappone, C, Pellegrini, G, Salzano, R, Casini, A, Milani, S & Del Rosso, M 2001, 'Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic system', Growth Factors, vol. 19, no. 2, pp. 87-100.
Fibbi, G. ; Pucci, M. ; D'Alessio, S. ; Grappone, C. ; Pellegrini, G. ; Salzano, R. ; Casini, A. ; Milani, S. ; Del Rosso, M. / Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic system. In: Growth Factors. 2001 ; Vol. 19, No. 2. pp. 87-100.
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AU - Fibbi, G.

AU - Pucci, M.

AU - D'Alessio, S.

AU - Grappone, C.

AU - Pellegrini, G.

AU - Salzano, R.

AU - Casini, A.

AU - Milani, S.

AU - Del Rosso, M.

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