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  • Title: Insulin-like growth factor-I enhances transforming growth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts.
    Author: Daian T, Ohtsuru A, Rogounovitch T, Ishihara H, Hirano A, Akiyama-Uchida Y, Saenko V, Fujii T, Yamashita S.
    Journal: J Invest Dermatol; 2003 Jun; 120(6):956-62. PubMed ID: 12787120.
    Abstract:
    Keloids are benign dermal tumors, characterized by invasive growth of fibroblasts and concomitant increased biosynthesis of extracellular matrix components, with unclear etiology. We previously demonstrated that keloid fibroblasts overexpress insulin-like growth factor-I receptor. In investigating the role of insulin-like growth factor-I receptor overexpression, insulin-like growth factor-I and transforming growth factor-beta interaction was examined in relation to extracellular matrix protein production in cultured human and mouse fibroblasts. Western blotting revealed that collagen type I was expressed in keloid and normal fibroblasts, and its expression was increased by transforming growth factor-beta stimulation more significantly in keloid rather than in normal fibroblasts. Insulin-like growth factor-I and transforming growth factor-beta1 costimulation markedly increased extracellular matrix proteins (collagen type I, fibronectin, and plasminogen activator inhibitor-1) compared with cultures with transforming growth factor-beta1 alone. Insulin-like growth factor-I treatment alone had no stimulatory effect. Real-time reverse transcription-polymerase chain reaction confirmed parallel collagen type I messenger RNA level changes. Luciferase assays were conducted to investigate intracellular signaling pathways in this synergistic stimulation using a mouse fibroblast cell line. Transforming growth factor-beta1 (1 or 10 ng per ml) increased the specific signaling activity approximately 10-fold, whereas the increase with insulin-like growth factor-I (100 ng per ml) was less than 2-fold compared with basal activity; however, the combination of transforming growth factor-beta1 and insulin-like growth factor-I resulted in an approximately 25-fold increase. Insulin-like growth factor-I markedly enhanced transforming growth factor-beta-induced phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor-2. Luciferase assay showed that this synergistic effect was attenuated by the p38 mitogen-activated protein kinase specific inhibitor SB203580 or phosphatidylinositol 3-kinase inhibitor wortmannin, but not by the mitogen-activated protein kinase/extracellular-signal-regulated protein kinase kinase inhibitor PD98059. These results indicate that insulin-like growth factor-I enhances transforming growth factor-beta-induced keloid formation through transforming growth factor-beta postreceptor signal cross-talk, mainly via the p38 mitogen-activated protein kinase/activating transcription factor-2 pathway.
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