Heparin-binding epidermal-growth-factor-like growth factor activation of keratinocyte ErbB receptors Mediates epidermal hyperplasia, a prominent side-effect of retinoid therapy.

Abstract

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.

• Authors: J Varani, M Zeigler, M K Dame, S Kang, G J Fisher, J J Voorhees, S W Stoll, J T Elder
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 117 Issue 6 Pg. 1335-41 (Dec 2001) ISSN: 0022-202X [Print] United States
• PMID: 11886492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies
• HBEGF protein, human
• Heparin-binding EGF-like Growth Factor
• Intercellular Signaling Peptides and Proteins
• Keratolytic Agents
• RNA, Messenger
• Receptors, Cell Surface
• Tretinoin
• Epidermal Growth Factor
• ErbB Receptors
• Calcium

Topics

• Adult
• Antibodies (pharmacology)
• Calcium (pharmacology)
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Epidermal Growth Factor (genetics, immunology, metabolism)
• Epidermis (drug effects, metabolism, pathology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Fibroblasts (cytology, drug effects)
• Gene Expression (drug effects)
• Heparin-binding EGF-like Growth Factor
• Humans
• Hyperplasia
• Intercellular Signaling Peptides and Proteins
• Keratinocytes (cytology, drug effects, metabolism)
• Keratolytic Agents (pharmacology)
• Organ Culture Techniques
• RNA, Messenger (metabolism)
• Receptors, Cell Surface
• Tretinoin (pharmacology)