Retinoid regulation of heparin-binding EGF-like growth factor gene expression in human keratinocytes and skin

Retinoic acid (RA) has profound effects on epidermal homeostasis; however, the molecular mechanisms by which retinoids regulate keratinocyte cell proliferation and differentiation are not well understood. Here we report that mRNA expression of heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF family of growth factors, is induced by RA in human keratinocytes and skin, and is overexpressed in the context of epidermal hyperplasia in vivo. Treatment of normal adult human keratinocytes with micromolar concentrations of RA significantly induced the expression of HB-EGF The response was efficiently blocked by specific inhibitors of ErbB tyrosine kinase activity, MAP kinase kinase (MEK), or p38 stress-activated protein kinase. RA also enhanced the induction of HB-EGF mRNA in human skin organ culture, an ex vivo model system displaying many similarities to wound healing in vivo. HB-EGF transcripts were markedly increased in human skin by topical treatment with RA under conditions known to provoke epidermal hyperplasia. HB-EGF transcripts were also markedly overexpressed in the hyperplastic epidermis of psoriatic lesions, relative to normal skin. These results support the hypothesis that the effects of RA on epidermal hyperplasia are mediated at least in part by HB-EGF, and suggest that signal transduction mechanisms other than or in addition to nuclear RA receptors contribute to this effect.