This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Kokot, A. Articles by Böhm, M. PubMed PubMed Citation Articles by Kokot, A. Articles by Böhm, M.

-Melanocyte-Stimulating Hormone Counteracts the Suppressive Effect of UVB on Nrf2 and Nrf-Dependent Gene Expression in Human Skin

Department of Dermatology and Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin (A.K., D.M., M.S., T.A.L., M.B.), University of Münster, 48149 Münster, Germany; Centre National de la Recherche Scientifique-Unité Mixte de Recherche 6061 (N.M., M.-D.G.), Institut de Génétique et Développement de Rennes, Equipe Régulation Transcriptionnelle, et Oncogenèse, Université de Rennes-1, Faculté de Médecine, Institut Fédératif de Recherche 140, 35402 Rennes, France; and Proclaim Parc d’Affaires de la Bretèche (N.M.), 35760 Saint-Gregoire, France

Address all correspondence and requests for reprints to: Markus Böhm, M.D., Associate Professor, Department of Dermatology, University of Münster, Von Esmarch-Strasse 58, 48149 Münster, Germany. E-mail: bohmm{at}uni-muenster.de.

Human skin is constantly exposed to UV light, the most ubiquitous environmental stressor. Here, we investigated the expression and regulation of Nrf1-3, transcription factors crucially involved in protection against oxidative stress in human skin cells in vitro, ex vivo, and in situ. In particular, we examined whether -MSH, a UV-induced peptide, is capable of modulating Nrf2 and Nrf-dependent gene expression. Nrf1, -2, and -3 were found to be expressed in various cutaneous cell types in vitro. Surprisingly, UVB irradiation at physiological doses (10 mJ/cm²) reduced Nrf2 and Nrf-dependent gene expression in normal keratinocytes and melanocytes in vitro as well as ex vivo in skin organ cultures. -MSH alone significantly increased Nrf2 as well as Nrf-dependent heme oxygenase-1, -glutamylcysteine-synthetase, and glutathione-S-transferase Pi gene expression in both keratinocytes and melanocytes. This effect of -MSH occurred at physiological doses and was due to transcriptional induction, mimicked by the artificial cAMP inducer forskolin, and blocked by protein kinase A pathway inhibition. In silico promoter analysis of Nrf2 further identified several putative binding sites for activator protein 1 and cAMP response element-binding protein, transcription factors typically activated by -MSH. Importantly, -MSH prevented or even overcompensated the UVB-induced suppression of Nrf2 and Nrf-dependent genes not only in normal keratinocytes and melanocytes in vitro but also in skin organ cultures. These findings, for the first time, show regulation of Nrf2 and Nrf-dependent genes by -MSH. Our data also highlight a novel facet in the cytoprotective and antioxidative effector mechanisms of -MSH and perhaps of related melanocortin peptides.