INSULIN-LIKE GROWTH-FACTOR-I AND EPIDERMAL GROWTH-FACTOR REGULATE INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-3 (IGFBP-3) IN THE HUMAN KERATINOCYTE CELL-LINE HACAT

The human keratinocyte cell line HaCaT has a basal phenotype and secre tes an insulin-like growth factor (IGF) binding protein, IGFBP-3, whic h modulates its IGF-I response. Keratinocytes are highly responsive to mitogenic stimulation by IGF-I and epidermal growth factor (EGF), but the effect of these growth factors on IGFBP secretion by keratinocyte s is not known. We investigated the effects of IGF-I and EGF, as well as three other skin-growth regulators, retinoic acid, basic fibroblast growth factor, and dexamethasone, on mitogenic stimulation and IGFBP- 3 production in HaCaT cell. IGF-I and EGF were strongly mitogenic, whe reas retinoic acid, basic fibroblast growth factor, and dexamethasone were not significantly mitogenic. IGF-I increased the level of IGFBP-3 in cell-conditioned medium by up to two-fold, whereas EGF caused a tw entyfold reduction in IGFBP-3. Retinoic acid and basic fibroblast grow th factor had only minor effects on IGFBP-3 and dexamethasone had no e ffect. IGF-I stimulation of IGFBP-3 did not involve increases in IGFBP -3 mRNA; however, EGF, consistent with its effect on IGFBP-3 protein, caused a fivefold reduction in IGFBP-3 mRNA. In summary, EGF profoundl y inhibited IGFBP-3 synthesis in basal keratinocytes, whereas IGF-I in creased IGFBP-3 levels by a posttranscriptional mechanism. We hypothes ize that by inhibiting IGFBP-3 production in basal keratinocytes, epid ermal mitogens such as EGF might stimulate epidermal growth indirectly by increasing local IGF-I availability.