Crosstalk between PDGF and IGF-I receptors in rat liver myofibroblasts: implication for liver fibrogenesis

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 α- and β-subunits were mainly expressed in hepatic stellate cells and LMFs, and were upregulated during their in vitro cultivation. In LMFs, PDGF-BB (10?ng/ml) stimulated DNA synthesis approximately two-fold 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 levels of IGF-IR and IRS-1 and inhibited the expression and activation of PDGFRα. PDGF-BB prevented IGF-I-induced downregulation 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, PI3 kinase and Akt kinase, whereas IGF-I demonstrated weaker effects. PLCγ1 was phosphorylated only in response to PDGF, but not to IGF-I. In rat LMFs, blockade of the IGF-IR via inhibition of the IGF-IR kinase completely abrogated IGF- and PDGF-induced mitogenesis and the ability of PDGF to phosphorylate PLCγ1. 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 downregulation of the IGF-IR. These interactions might be relevant in vivo for the fibroproliferative response during liver injury.