Inhibitory effect of soluble PDGF-beta receptor in culture-activated hepatic stellate cells |
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Authors: | Borkham-Kamphorst Erawan Stoll Doris Gressner Axel M Weiskirchen Ralf |
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Institution: | Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen D-52074, Germany. |
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Abstract: | Following liver injury, hepatic stellate cells undergo phenotypic transformation with acquisition of myofibroblast-like features, characterized by increased cell proliferation, motility, contractility, and extracellular matrix production. Activation of hepatic stellate cells is regulated by several cytokines and growth factors, including platelet-derived growth factor B-chain, a potent mitogen for HSC, overexpressed during hepatic fibrogenesis. This pleiotropic mediator exerts cellular effects by binding to specific receptors, inducing receptor dimerization and tyrosine-autophosphorylation. Activated receptor phosphotyrosines recruit signal transduction molecules, initiating various signaling pathways. We produced a soluble PDGFbeta-receptor (sPDGFRbeta) consisting of an extracellular domain connected to the IgG-Fc part of human immunoglobulin heavy chain. This soluble, chimeric receptor inhibits PDGF signaling and PDGF-induced proliferation in culture-activated hepatic stellate cells. Furthermore, sPDGFR decreased collagen type I (alphaI) mRNA expression and inhibits autocrine-looping in PDGF-BB mRNA production. In summary, sPDGFRbeta clearly shows effective inhibitory properties in early HSC activation, suggesting potential therapeutic impact for anti-PDGF intervention in liver fibrogenesis. |
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Keywords: | Adenovirus Gene transfer α-SMA Collagen type I (αI) Fibrosis Hepatic stellate cell Myofibroblast PDGF PDGFR sPDGFRβ Soluble receptor TGF-β1 |
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