BACKGROUND AND AIMS: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth factor beta (TGF-beta) but little is known of the expression patterns and functions of TSP-1 in liver cells. We therefore analysed if and how TSP-1 acts on TGF-beta during fibrogenesis. METHODS AND RESULTS: Using reverse transcription-polymerase chain reaction, we demonstrated that hepatocytes from normal liver expressed no TSP-1 mRNA whereas Kupffer cells and sinusoidal endothelial cells did. TSP-1 mRNA and protein were detected in quiescent and activated cultured hepatic stellate cells (HSC) and TSP-1 expression was highly inducible by platelet derived growth factor BB (PDGF-BB) and, to a lesser extent, by tumour necrosis factor alpha in activated HSC. Furthermore, addition of PDGF-BB directly led to enhanced TGF-beta mRNA expression and a TSP-1 dependent increase in TGF-beta/Smad signalling. Using either a peptide specifically blocking the interaction of TSP-1 with latent TGF-beta or antibodies against TSP-1 not only abrogated activation of latent TGF-beta but also reduced the effects of the active dimer itself. CONCLUSIONS: Our data suggest that TSP-1 expression is important for TGF-beta effects and that it is regulated by the profibrogenic mediator PDGF-BB in HSC. Furthermore, the presence of TSP-1 seems to be a prerequisite for effective signal transduction by active TGF-beta not only in rat HSC but also in other cell types such as human dermal fibroblasts.
BACKGROUND AND AIMS: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth factor beta (TGF-beta) but little is known of the expression patterns and functions of TSP-1 in liver cells. We therefore analysed if and how TSP-1 acts on TGF-beta during fibrogenesis. METHODS AND RESULTS: Using reverse transcription-polymerase chain reaction, we demonstrated that hepatocytes from normal liver expressed no TSP-1 mRNA whereas Kupffer cells and sinusoidal endothelial cells did. TSP-1 mRNA and protein were detected in quiescent and activated cultured hepatic stellate cells (HSC) and TSP-1 expression was highly inducible by platelet derived growth factor BB (PDGF-BB) and, to a lesser extent, by tumour necrosis factor alpha in activated HSC. Furthermore, addition of PDGF-BB directly led to enhanced TGF-beta mRNA expression and a TSP-1 dependent increase in TGF-beta/Smad signalling. Using either a peptide specifically blocking the interaction of TSP-1 with latent TGF-beta or antibodies against TSP-1 not only abrogated activation of latent TGF-beta but also reduced the effects of the active dimer itself. CONCLUSIONS: Our data suggest that TSP-1 expression is important for TGF-beta effects and that it is regulated by the profibrogenic mediator PDGF-BB in HSC. Furthermore, the presence of TSP-1 seems to be a prerequisite for effective signal transduction by active TGF-beta not only in rat HSC but also in other cell types such as human dermal fibroblasts.
Authors: P J de Bleser; P Jannes; S C van Buul-Offers; C M Hoogerbrugge; C F van Schravendijk; T Niki; V Rogiers; J L van den Brande; E Wisse; A Geerts Journal: Hepatology Date: 1995-05 Impact factor: 17.425
Authors: S E Crawford; V Stellmach; J E Murphy-Ullrich; S M Ribeiro; J Lawler; R O Hynes; G P Boivin; N Bouck Journal: Cell Date: 1998-06-26 Impact factor: 41.582
Authors: Heng-Hong Li; John B Tyburski; Yi-Wen Wang; Steve Strawn; Bo-Hyun Moon; Bhaskar V S Kallakury; Frank J Gonzalez; Albert J Fornace Journal: Alcohol Clin Exp Res Date: 2014-04-28 Impact factor: 3.455
Authors: Lata Mukundan; Justin I Odegaard; Christine R Morel; Jose E Heredia; Julia W Mwangi; Roberto R Ricardo-Gonzalez; Y P Sharon Goh; Alex Red Eagle; Shannon E Dunn; Jennifer U H Awakuni; Khoa D Nguyen; Lawrence Steinman; Sara A Michie; Ajay Chawla Journal: Nat Med Date: 2009-10-18 Impact factor: 87.241