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 a-and b-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 PDGFRa. 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. PLCc 1 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 PLCc 1 . 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.

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

“…These findings extend and confirm data derived from earlier studies of clonal HSC lines, in which Shh antibodies increased cellular apoptosis and recombinant Shh stimulated growth [29]. The present study also demonstrates that proliferative actions of PDGF-BB, a major HSC mitogen [45,46], are mediated via the Hh pathway because three distinct approaches that abrogate Hh signaling each significantly inhibited PDGF-related increases in HSC incorporation of BrdU. Both agents that specifically antagonize Hh signaling by preventing activation of discrete Hh pathway signaling components (Anti-Shh antibodies prevent Shh from activating Ptc, and cyclopamine prevents Ptc from activating Smo) [60], exerted comparable effects on HSC DNA synthesis, reducing the stimulatory actions of PDGF-BB by about 50%.…”

“…Therefore, subsequent studies addressed the effect of AKT activation on HSC expression of Shh. As expected [32,45,46], PDGF-BB elicited rapid phosphorylation of AKT on Thr308 and Ser473, with peak AKT activation occurring within the initial hour after PDGF-BB addition (Fig 4A). The ensuing accumulation of Shh protein was inhibited by addition of either the PI3 kinase inhibitor, Ly294002, which inhibits PDGF-BB activation of AKT [45] (Fig 4B) or adenovirally-mediated delivery of dominant negative AKT (Ad5dnAkt) (Fig 4C).…”

“…PDGF-BB-activation of AKT mediates PDGF-BB's trophic actions [32,45,46]. Therefore, subsequent studies addressed the effect of AKT activation on HSC expression of Shh.…”

Use of insulin-like growth factor in the healing of open wounds in diabetic and non-diabetic rats

“…Recent studies have reported the mitogenic action of myofibroblast differentiation and proliferation by IGF-1 8,9 .…”

Pathogenesis of equine endometrosis: Relevance of the growth factors transforming growth factor- a, -b1, -b2 and -b3 and matrixmetalloproteinase-2

“…der aktiven nichtdestruierenden Endometrosen) und TGF-b1 (nur inaktiven Endometrosen (Raila 2000). Stromal synthetisierte profibrotische Wachstumsfaktoren und Zytokine, wie beispielsweise PDGF, TNF-a, CTGF u.a., die bei verschiedenen Gewebsfibrosen nachgewiesen wurden (Antoniades et al 1990, Kapanci et al 1995, Leask et al 2002, Novosyadlyy et al 2006 Zusammenfassend kann festgestellt werden, dass eine mit der Leber-und Lungenfibrose vergleichbare Schlüsselrolle der TGF-Wachstumsfaktoren in der Pathogenese der equinen Endometrose anhand der vorliegenden Ergebnisse dieser Arbeit nicht eindeutig belegt werden kann. Eine generell erhöhte epitheliale und/oder stromale TGF-Wachstumsfaktor-Expression im Sinne einer "überschießenden" Wundheilungsreaktion wurde in der equinen Endometrose nicht nachgewiesen.…”