PDGF-BB REGULATES IGF-MEDIATED IGFBP-4 PROTEOLYSIS IN FETAL LUNG FIBROBLASTS

Insulin-like growth factor (IGF)-stimulated lung fibroblast proliferation may be regulated by locally produced IGF-binding proteins (IGFBPs) during lung development. Recent evidence has shown that many growth factors participate in the regulation of cell proliferation by regulating IGFBPs. Because platelet-derived growth factor-BB (PDGF-BB)is highly expressed during lung development and is known to regulate IGFBP-4 production bylung cells, we examined the mechanisms by which PDGF-BB regulates IGFBP-4 production using primary cultures of 19-day gestation rat lung fibroblasts. Exposure of fetal rat lung fibroblasts to PDGF-BB increased IGFBP-4 mRNA transcript abundance by 3.6- and 2.4-fold at 18 and 40 hours, respectively. Addition of Rp-adenosine 3'-5'-cyclic monophosphothioa tetriethylamine (rp-cAMPS),a competitive inhibitor of protein kinase A, blunted the PDGF-BB-stimulated increase in conditioned medium (CM)IGFBP-4 and the increase in IGFBP-4 mRNA. Proteolysis of IGFBP-4 was detected in aliquots of cell-free CM from cells exposed to SFMfor 48 hours. IGFBP-4 proteolysis was inhibited by EDTA and 1,10-phenanthroline and was accentuated by the addition of IGF-I and IGF-IIand, to a lesser extent, by des(1-3)IGF-I. Exposure of cells to PDGF-BB for 48 hours resulted in an inhibition of IGFBP-4 proteolysis that was associated with a decrease in the concentration of IGF-I in CM. These studies demonstrate that PDGF-BB increases the accumulation of IGFBP-4 in fetal rat lung fibroblasts CM through increased production and by inhibiting IGF-mediated IGFBP-4 proteolysis.