Transforming growth factor‐β1 regulates platelet‐derived growth factor receptor β subunit in human liver fat‐storing cells
ABSTRACT Activated liver fat-storing cells (FSC) are known to play a key role in the development of liver fibrosis. An important element in FSC activation process is the increased expression of receptors for platelet-derived growth factor (PDGF), a potent mitogen for FSC. The aim of the present study was to evaluate the expression PDGF-receptor alpha and beta subunits in cultured human FSC and their regulation induced by transforming growth factor-β1 (TGF-β), a cytokine potentially involved in an autocrine loop. TGF-β induced a significant increase of the mitogenic effect of PDGF-BB and did not affect the mitogenicity of PDGF-AA and PDGF-AB, suggesting a selective action of the PDGF-receptor-β subunit. This hypothesis was confirmed by regulation experiments showing selective and time-dependent upregulation of the messenger (m)RNA encoding for the PDGF-receptor-β subunit and the relative protein induced by TGF-β. In addition, binding studies showed a parallel increase of PDGF-BB binding sites after incubation of human FSC with TGF-β. These studies provide evidence for an additional mechanism leading to the perpetuation of FSC activation and proliferation and contribute to a better understanding of the role of TGF-β and PDGF in the development of liver fibrosis. (Hepatology 1995;21:232–239).
- Clinical Neurophysiology 06/2011; 122. · 2.98 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Background/Aims: Transforming growth factor-β (TGF-β) is considered to be an important mediator in the development of fibrosis in several chronic liver diseases. To understand the mechanism(s) by which TGF-β exerts its action(s), we investigated the cellular distribution of TGF-β1,2,3 transcripts in normal and carbon tetrachloride (CCl4)-induced fibrotic rat liver.Methods: Parenchymal, sinusoidal endothelial, Kupffer and stellate cells were isolated and purified. The exact cellular composition of each isolate was determined by transmission electron microscopy. Expression of TGF-β1,2,3 transcripts was investigated using Northern hybridization analysis. Hybridization signals were quantified by scanning densitometry and corrected for: (i) differences in extractable RNA per cell type, (ii) signal contribution from contaminating cells, and (iii) differences in loading, capillary transfer and hybridization.Results: In normal liver, TGF-β1 mRNA was predominantly expressed in Kupffer cells, exhibiting values approximately 9-fold higher than those in stellate cells. No expression was found in endothelial and parenchymal cells. Signals for TGF-β2 and TGF-β3 were much weaker when compared to TGF-β1. In Kupffer cells, the level of TGF-β2 was approximately 4-fold higher than in stellate cells. Little expression was found in endothelial cells. TGF-β3 expression could only be detected in stellate cells. TGF-β2 and TGF-β3 was not expressed in parenchymal cells. In fibrotic liver, TGF-β1 mRNA was strongly expressed in all the sinusoidal cells. TGF-β2 and TGF-β3 could no longer be detected. When compared to the level of expression in normal stellate cells, the level of TGF-β1 increased 12-fold in stellate cells from fibrotic livers, and 6-fold in endothelial cells. In Kupffer cells, the level of expression remained unchanged.Conclusions: (i) In both normal and fibrotic liver, TGF-β1 is the most abundant isoform, (ii) in normal liver, TGF-β1 is expressed strongly by Kupffer cells and moderately by stellate cells, TGF-β2 expression is highest in Kupffer cells, followed by stellate cells and endothelial cells. TGF-β3 is expressed by stellate cells, (iii) in fibrotic liver, the level of TGF-β1 expression increases selectively in stellate cells and endothelial cells. This suggests an important role, not only for stellate, but also for endothelial cells in fibrogenesis.Journal of Hepatology 04/1997; 26(4):886-893. · 10.40 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: In the early atherosclerotic lesion, monocytes accumulate at sites of inflammation and endothelial injury. Platelet-derived growth factor (PDGF), produced for example by macrophages, is a chemoattractant for smooth muscle cells and possibly also for macrophages. During early differentiation into macrophages, human monocytes (early hMDM) showed lower expression of PDGF α-receptor (PDGF-Rα) than β-receptor (PDGF-Rβ) mRNA. Early hMDM showed increased random motility (chemokinesis) in the presence of PDGF of the long (BBL) but not short (BBS) B-chain homodimer. Neither PDGF-AAS nor PDGF-AAL affected early hMDM motility. Since increased cytokine levels accompany inflammation, the influence of interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) on PDGF-R expression and migratory response were studied. Only PDGF-Rα mRNA was highly upregulated by IFN-γ. TGF-β only had minor effects on receptor mRNAs. Upregulation of PDGF-Rα levels by IFN-γ was accompanied by significantly increased migration (chemotaxis) towards PDGF-AAL only. Consequently, IFN-γ modulates PDGF-Rs expression in early hMDM and, subsequently, the chemotactic activity of PDGF-AAL on IFN-γ-stimulated early hMDM. This suggests that PDGF-AAL may be involved in attracting activated monocytes to sites of inflammation and injury.Atherosclerosis 01/2001; 156(2):267-275. · 3.71 Impact Factor