Inhibitory effect of soluble PDGF-beta receptor in culture-activated hepatic stellate cells.
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.
Borkham-Kamphorst
Erawan
E
Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen D-52074, Germany.
Stoll
Doris
D
Gressner
Axel M
AM
Weiskirchen
Ralf
R
D000595:Amino Acid Sequence; D000818:Animals; D000077214:Becaplermin; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003470:Culture Media; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism*; D007074:Immunoglobulin G; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility
D003470:Culture Media; D007074:Immunoglobulin G; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta