Inhibitory effect of soluble PDGF-β receptor in culture-activated hepatic stellate cells

• Published in: Biochemical and biophysical research communications Vol. 317; no. 2; pp. 451 - 462
• Main Authors: Borkham-Kamphorst, Erawan, Stoll, Doris, Gressner, Axel M., Weiskirchen, Ralf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.04.2004
• Subjects: Adenovirus; Amino Acid Sequence; Animals; Cells, Cultured; Cercopithecus aethiops; Collagen type I (αI); COS Cells; Culture Media; Disease Models, Animal; Fibrosis; Gene transfer; Hepatic stellate cell; Hepatocytes - metabolism; Immunoglobulin G; Liver Cirrhosis - metabolism; Male; Molecular Sequence Data; Mutation; Myofibroblast; PDGF; PDGFR; Platelet-Derived Growth Factor - metabolism; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor beta - chemistry; Receptor, Platelet-Derived Growth Factor beta - isolation & purification; Receptor, Platelet-Derived Growth Factor beta - metabolism; Signal Transduction; Solubility; Soluble receptor; sPDGFRβ; TGF-β1; α-SMA; α-SMA; Soluble receptor; Gene transfer; Adenovirus; Myofibroblast; PDGF; Fibrosis; PDGFR; sPDGFRβ; TGF-β1; Collagen type I (αI); Hepatic stellate cell
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2004.03.064

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 PDGFβ-receptor (sPDGFRβ) 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 (αI) mRNA expression and inhibits autocrine-looping in PDGF-BB mRNA production. In summary, sPDGFRβ clearly shows effective inhibitory properties in early HSC activation, suggesting potential therapeutic impact for anti-PDGF intervention in liver fibrogenesis.