Article Text
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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- 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
Footnotes
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Conflict of interest: None declared.