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Thrombospondin 1 acts as a strong promoter of transforming growth factor β effects via two distinct mechanisms in hepatic stellate cells
  1. K Breitkopf1,
  2. I Sawitza2,
  3. J H Westhoff2,
  4. L Wickert2,
  5. S Dooley1,
  6. A M Gressner2
  1. 1Department of Medicine II, Mol Alcohol Research in Gastroenterology, University Hospital of Heidelberg at Mannheim, Mannheim, Germany
  2. 2Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany
  1. Correspondence to:
    Dr K Breitkopf
    Department of Medicine II, University Hospital Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; katja.breitkopfmed.ma.uni-heidelberg.de

Abstract

Background and aims: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth factor β (TGF-β) 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-β 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 α in activated HSC. Furthermore, addition of PDGF-BB directly led to enhanced TGF-β mRNA expression and a TSP-1 dependent increase in TGF-β/Smad signalling. Using either a peptide specifically blocking the interaction of TSP-1 with latent TGF-β or antibodies against TSP-1 not only abrogated activation of latent TGF-β but also reduced the effects of the active dimer itself.

Conclusions: Our data suggest that TSP-1 expression is important for TGF-β 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-β not only in rat HSC but also in other cell types such as human dermal fibroblasts.

  • TGF-β, transforming growth factor β
  • PDGF-BB, platelet derived growth factor BB
  • TSP, thrombospondin
  • HSC, hepatic stellate cells
  • MFB, myofibroblasts
  • SEC, sinusoidal endothelial cell
  • TNF-α, tumour necrosis factor α
  • IL-6, interleukin 6
  • LAP, latency associated peptide
  • LTBP, latent TGF-β binding protein
  • RT-PCR, reverse transcription-polymerase chain reaction
  • FCS, fetal calf serum
  • BDL, bile duct ligation
  • transforming growth factor
  • platelet derived growth factor
  • tumour necrosis factor
  • liver
  • fibrosis
  • thrombospondin
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Footnotes

  • Conflict of interest: None declared.

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