INDUCTION OF AUTOCRINE EPIDERMAL GROWTH-FACTOR RECEPTOR LIGANDS IN HUMAN KERATINOCYTES BY INSULIN INSULIN-LIKE GROWTH-FACTOR-I

Autocrine activation of the epidermal growth factor (EGF) receptor on keratinocytes has been recognized as an important growth regulatory me chanism involved in epithelial homeostasis, and, possibly, hyperprolif erative diseases. Insulin-like growth factor (IGF)-1 and insulin have been shown to be paracrine keratinocyte mitogens that bind to the type I IGF receptor which is expressed on actively proliferating keratinoc ytes in situ. In this report, we demonstrate that ICF-1/insulin induce d production of keratinocyte-derived autocrine growth factors that bin d to the EGF receptor. Increased steady-state mRNA levels for transfor ming growth factor alpha (TGF-alpha) and for amphiregulin (AR) were ob served upon incubation of keratinocytes with mitogenic concentrations of ICF-1. IGF-1 also induced production and secretion of TGF-alpha and AR proteins as detected by immunoassays. An EGF receptor antagonistic monoclonal antibody abolished the mitogenic effect of IGF-1 on cultur ed keratinocytes. These results suggest that stimulation of keratinocy te growth by IGF-1 requires activation of an EGF receptor-mediated aut ocrine loop. (C) 1995 Wiley-Liss, Inc.