Abstract
Insulin-like growth factor I (IGF-I) and platelet-derived growth factor (PDGF) have been identified as significant mitogens for liver myofibroblasts (LMFs), one of the cell populations playing a role in liver fibrogenesis. In the present work we aimed to elucidate a possible interaction between PDGF receptor (PDGFR) and IGF-I receptor (IGF-IR) signaling in LMFs. Among different rat liver cells, PDGFR alpha- and beta-subunits were mainly expressed in hepatic stellate cells and LMFs, and were up-regulated during their in vitro cultivation. PDGF-BB (10 ng/mL) stimulated DNA synthesis approximately two-fold in LMFs and this effect was similar to that of IGF-I. IGF-I and PDGF-BB differentially affected IGF-IR and PDGFR signaling. High concentrations of IGF-I decreased IGF-IR and its principal docking protein IRS–1 as well as inhibited expression and activation of PDGFR-alpha. PDGF-BB prevented IGF-I-induced down-regulation of the IGF-IR, but did not affect expression of its cognate receptor subunits. Transphosphorylation of PDGFR and IGF-IR was not observed. PDGF effectively activated terminal MAP kinases (ERK1/2, p38 MAPK, JNK–1), in contrast to IGF-I, which demonstrated only weak effects. PLC-gamma–1 was activated only in response to PDGF, but not to IGF-I. Blockade of the IGF-IR via inhibition of the IGF-IR kinase completely abrogated IGF- and PDGF-induced mitogenesis of rat LMFs as well as the ability of PDGF to stimulate PLC-gamma–1 activity. In conclusion, the presented data demonstrate that the PDGFR signaling requires a functional IGF-IR and that PDGF-BB stabilizes the IGF-IR function through preventing the IGF-I-induced down-regulation of the IGF-IR. These interactions might be relevant in vivo for the fibroproliferative response during liver injury.
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