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RECEPTORS AND SIGNAL TRANSDUCTION

17-Estradiol enhances heparin-binding epidermal growth factor-like growth factor production in human keratinocytes

Department of Dermatology, Teikyo University, School of Medicine, Itabashi-Ku, Tokyo, Japan

Submitted 1 October 2004 ; accepted in final form 1 December 2004

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) enhances reepithelialization in wounds. Estrogen is known to promote cutaneous wound repair. We examined the in vitro effects of 17-estradiol (E₂) on HB-EGF production by human keratinocytes. E₂ or membrane-impermeable BSA-conjugated E₂ (E₂-BSA) increased HB-EGF secretion, mRNA level, and promoter activity in keratinocytes. E₂ or E₂-BSA enhanced in vitro wound closure in keratinocytes, and the closure was suppressed by anti-HB-EGF antibody. Activator protein-1 (AP-1) and specificity protein 1 (Sp1) sites on HB-EGF promoter were responsible for the E₂- or E₂-BSA-induced transactivation. Antisense oligonucleotides against c-Fos, c-Jun, and Sp1 blocked E₂- or E₂-BSA-induced HB-EGF transactivation. E₂ or E₂-BSA enhanced DNA binding and transcriptional activity of AP-1 and generated c-Fos/c-Jun heterodimers by inducing c-Fos expression. E₂ or E₂-BSA enhanced DNA binding and transcriptional activity of Sp1 in parallel with the enhancement of Sp1 phosphorylation. These effects of E₂ or E₂-BSA were not blocked by the nuclear estrogen receptor antagonist ICI-182,780 or anti-estrogen receptor- or - antibodies but were blocked by inhibitors of G protein, phosphatidylinositol-specific PLC, PKC-, and MEK1. These results suggest that E₂ or E₂-BSA may enhance HB-EGF production via activation of AP-1 and Sp1. These effects of E₂ or E₂-BSA may be dependent on membrane G protein-coupled receptors different from nuclear estrogen receptors and on the receptor-mediated activities of phosphatidylinositol-specific PLC, PKC-, and MEK1. E₂ may enhance wound reepithelialization by promoting HB-EGF production in keratinocytes.

activator protein-1; specificity protein 1; transcription; G protein

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				N. Kanda and S. Watanabe Histamine enhances the production of human -defensin-2 in human keratinocytes Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1916 - C1923. [Abstract] [Full Text] [PDF]