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 by lung cells, we examined the mechanisms by which PDGF-BB regulates ICFBP-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 monophosphothioate triethylamine (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 SFM for 48 hours. IGFBP-4 proteolysis was inhibited by EDTA and 1,10-phenanthroline and was accentuated by the addition of IGF-I and IGF-II and, 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 ICFBP-4 in fetal rat lung fibroblasts CM through increased production and by inhibiting IGF-mediated IGFBP-4 proteolysis.
Price
W A
WA
Department of Pediatrics, University of North Carolina at Chapel Hill, 27599, USA. waprice@unc.edu
D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D010446:Peptide Fragments / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000494:pharmacology
D017077:Culture Media, Conditioned; D018974:Insulin-Like Growth Factor Binding Protein 4; D010446:Peptide Fragments; D010618:Phenanthrolines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D013873:Thionucleotides; C058957:insulin-like growth factor 1, des-(1-3)-; D000077214:Becaplermin; C016957:adenosine-3',5'-cyclic phosphorothioate; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D004492:Edetic Acid; D000242:Cyclic AMP; C025205:1,10-phenanthroline