Retinoid-induced epidermal hyperplasia is mediated by epidermal growth factor receptor activation via specific induction of its ligands heparin-binding EGF and amphiregulin in human skin in vivo
Retinoid-induced epidermal hyperplasia is mediated by epidermal growth factor receptor activation via specific induction of its ligands heparin-binding EGF and amphiregulin in human skin in vivo
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DOI：
10.1038/sj.jid.5700202
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发表时间：
2006-04-01
影响因子：
6.5
通讯作者：
Fisher, Gary J.
中科院分区：
文献类型：
--
作者：
Rittie, Laure;Varani, James;Fisher, Gary J.
类维生素A广泛用于治疗光老化以刺激皮肤修复。然而，类维生素A也会诱导表皮增生，这可能导致过度鳞屑。结垢是局部维甲酸治疗的主要障碍。表皮生长因子受体的配体激活强烈刺激角质形成细胞的生长。我们研究了类维生素A对EGFR配体的调节以及EGFR在体内类维生素A诱导的人类皮肤增生中的作用。用全反式视黄酸（tRA）局部治疗人类皮肤诱导EGFR配体肝素结合（HB）-EGF和双调蛋白（AR），并降低β细胞素mRNA水平。激光捕获显微切割耦合实时逆转录PCR显示，tRA增加HB-EGF mRNA在整个表皮，而AR诱导仅限于基底角质形成细胞。局部tRA在体内激活人皮肤中细胞外信号调节激酶1/2（Erk1/2）下游EGFR效应子tRA增加AR和HB-EGF蛋白的可溶性形式，并诱导人皮肤器官培养物中的表皮发育不全。用特异性抗体中和HB-EGF或AR可强烈减少tRA诱导的表皮增生。最后，染料木黄酮抑制EGFR活化可减少局部类维生素A治疗引起的表皮增生。这些数据证明了EGFR活化在类维生素A诱导的表皮增生中的核心作用，并表明EGFR抑制剂可以减轻类维生素A诱导的结垢。
Retinoids are widely used in the treatment of photoaging to stimulate dermal repair. However, retinoids also induce epidermal hyperplasia, which can lead to excessive scaling. Scaling is the major deterrent to topical retinoid therapy. Keratinocyte growth is strongly stimulated via ligand activation of EGFR. We examined regulation of EGFR ligands by retinoids and the role of EGFR in retinoid-induced hyperplasia in human skin in vivo. Topical treatment of human skin with all-trans retinoic acid (tRA) induces EGFR ligands heparin-binding (HB)-EGF and amphiregulin (AR), and reduces betacellulin mRNA levels. Laser capture microdissection-coupled real-time reverse transcription-PCR reveals that tRA increases HB-EGF mRNA throughout the epidermis, whereas AR induction is limited to basal keratinocytes. Topical tRA activates extracellular signal-regulated kinase 1/2 (Erk1/2) downstream EGFR effectors in human skin in vivo. tRA increases the soluble forms of AR and HB-EGF proteins, and induces epidermal hyplasia, in human skin organ culture. Neutralization of HB-EGF or AR with specific antibodies strongly reduces tRA-induced epidermal hyperplasia. Finally, inhibition of EGFR activation by genistein reduces epidermal hyperplasia caused by topical retinoid treatment. These data demonstrate the central role of EGFR activation in retinoid- induced epidermal hyperplasia, and suggest that EGFR inhibitors can mitigate retinoid-induced scaling.