Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro.
Keloids are proliferative dermal growths representing a pathological wound-healing response. We report high proliferation rates in normal (NF) and keloid-derived fibroblasts (KF) cocultured with keloid-derived keratinocytes (KK). IGF binding protein (IGFBP)-3 mRNA and secreted IGFBP-3 in conditioned media were increased in NF cocultured with KK compared with NF but markedly reduced in KF cocultured with KK or normal keratinocytes (NK). IGFBP-2 and IGFBP-4 mRNA levels were elevated, whereas IGFBP-5 mRNA was decreased in KF cocultured with KK or NK. Significant increases in IGFBP-2 and -4 mRNA in KF cocultured with KK did not correlate with protein secretion. Downstream IGF signaling cascade components, phospho-Raf, phospho-MEK1/2, phospho-MAPK, PI-3 kinase, phospho-Akt, and phospho-Elk-1, were elevated in KF cocultured with KK. Addition of recombinant human IGFBP-3 or antibodies against IGF-I or IGF-IR significantly inhibited proliferation of KF. The bioavailability of IGF-I may be related to the levels of IGFBP-3 produced, which in turn influences KF proliferation, suggesting that modulation of IGF-I, IGF-IR, and IGFBP-3, individually or in combination, may represent novel approaches to the treatment of keloids.
Phan
Toan-Thang
TT
National Burns Centre, Singapore General Hospital, Singapore 169608.
Lim
Ivor Jiun
IJ
Bay
Boon Huat
BH
Qi
Robert
R
Longaker
Michael Thornton
MT
Lee
Seng-Teik
ST
Huynh
Hung
H
D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000276:immunology; D007627:Keloid / Q000473:pathology* / Q000503:physiopathology*; D015603:Keratinocytes / Q000502:physiology*; D008934:Mitogens / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D013002:Somatomedins / Q000378:metabolism*
D000906:Antibodies; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D008934:Mitogens; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1