¹Cell and Tissue Laboratory, URPHYM, University of Namur (FUNDP), Namur, Belgium

Correspondence: Professor Yves Poumay, Cell and Tissue Laboratory, URPHYM, University of Namur, 61, rue de Bruxelles, B-5000 Namur, Belgium. E-mail: yves.poumay@fundp.ac.be

Received 27 November 2006; Revised 18 July 2007; Accepted 24 July 2007; Published online 11 October 2007.

Abstract

Epidermal homeostasis and repair of the skin barrier require that epidermal keratinocytes respond to alterations of their environment. We report that cellular stress with methyl--cyclodextrin (MBCD), a molecule that extracts membrane cholesterol and thereby disrupts the structure of lipid rafts, strongly induces the synthesis of heparin-binding EGF-like growth factor (HB-EGF) in keratinocytes through the activation of p38 mitogen-activated protein kinase. Interesting parallels between lipid raft disruption and oxidative stress can be drawn as hydrogen peroxide induces p38 activation and HB-EGF synthesis in keratinocytes. Consistent with other studies, we show increased HB-EGF expression in keratinocytes located at the margin of wounded skin areas. Analyzing cultured keratinocytes exposed to rhHB-EGF, we report increased HB-EGF mRNA levels and alterations in the expression of differentiation markers. Interestingly, identical alterations in differentiation markers are shown to occur in vivo at the wound margin and in HB-EGF-treated cultures. In addition, in vitro sectioning of skin samples also induces the expression of HB-EGF at the border of the incisions. Altogether, our data suggest that expression of HB-EGF is a marker of the keratinocyte's response to a challenging environment and demonstrate that this growth factor alters the phenotype of keratinocytes in a manner similar to that observed during epidermal repair.