Heparin-binding EGF-like growth factor is induced by disruption of lipid rafts and oxidative stress in keratinocytes and participates in the epidermal response to cutaneous wounds.
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-beta-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.
Mathay
Conny
C
Cell and Tissue Laboratory, URPHYM, University of Namur (FUNDP), Namur, Belgium.
Giltaire
Séverine
S
Minner
Frédéric
F
Bera
Emilie
E
Hérin
Michel
M
Poumay
Yves
Y
D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000293:injuries* / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D053550:Keratin-10 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D021962:Membrane Microdomains / Q000502:physiology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015415:Biomarkers; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C507493:KRT10 protein, human; D011498:Protein Precursors; D053550:Keratin-10; C032253:involucrin; D004815:Epidermal Growth Factor; D002784:Cholesterol; D048051:p38 Mitogen-Activated Protein Kinases