Heparin-binding epidermal-growth-factor-like growth factor activation of keratinocyte ErbB receptors Mediates epidermal hyperplasia, a prominent side-effect of retinoid therapy.
Sun-protected human skin was maintained in organ culture and treated with all-trans retinoic acid in the presence or absence of reversible or irreversible pharmacologic antagonists of c-erbB receptor tyrosine kinase activity. In the absence of these inhibitors, all-trans retinoic acid induced epidermal hyperplasia comparable to that induced in intact skin by all-trans retinol or all-trans retinoic acid itself. There was a strong correlation between inhibition of epidermal hyperplasia in organ culture and inhibition of epidermal-growth-factor-dependent keratinocyte growth in monolayer culture. In additional studies it was shown that all-trans retinoic acid could overcome the known inhibitory effects of calcium on expression of HB-EGF-like growth factor mRNA in organ-cultured skin. Further, it was shown that an antibody to HB-EGF-like growth factor inhibited retinoid-stimulated epidermal hyperplasia in organ culture and reduced proliferation in cultured keratinocytes. In contrast, the c-erbB receptor tyrosine kinase antagonists and the neutralizing HB-EGF-like growth factor antibody were ineffective in inhibiting all-trans-retinoic-acid-dependent survival and proliferation of human dermal fibroblasts. Taken together, these data indicate (i) that retinoid-induced epidermal hyperplasia in human skin proceeds through c-erbB, and (ii) that HB-EGF-like growth factor is one of the c-erbB ligands mediating this effect.
Varani
J
J
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. varani@umich.edu
Zeigler
M
M
Dame
M K
MK
Kang
S
S
Fisher
G J
GJ
Voorhees
J J
JJ
Stoll
S W
SW
Elder
J T
JT
D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007641:Keratolytic Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface; D014212:Tretinoin / Q000494:pharmacology*
D000906:Antibodies; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007641:Keratolytic Agents; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014212:Tretinoin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D002118:Calcium