Alpha-melanocyte-stimulating hormone counteracts the suppressive effect of UVB on Nrf2 and Nrf-dependent gene expression in human skin.
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 alpha-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/cm(2)) reduced Nrf2 and Nrf-dependent gene expression in normal keratinocytes and melanocytes in vitro as well as ex vivo in skin organ cultures. alpha-MSH alone significantly increased Nrf2 as well as Nrf-dependent heme oxygenase-1, gamma-glutamylcysteine-synthetase, and glutathione-S-transferase Pi gene expression in both keratinocytes and melanocytes. This effect of alpha-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 alpha-MSH. Importantly, alpha-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 alpha-MSH. Our data also highlight a novel facet in the cytoprotective and antioxidative effector mechanisms of alpha-MSH and perhaps of related melanocortin peptides.
Kokot
Agatha
A
Department of Dermatology, Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, Von Esmarch-Strasse 58, 48149 Münster, Germany.
Metze
Dieter
D
Mouchet
Nicolas
N
Galibert
Marie-Dominique
MD
Schiller
Meinhard
M
Luger
Thomas A
TA
Böhm
Markus
M
D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D051266:Nuclear Respiratory Factor 1 / Q000502:physiology*; D009924:Organ Culture Techniques; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D014466:Ultraviolet Rays; D015854:Up-Regulation; D000521:alpha-MSH / Q000494:pharmacology*
D050976:Basic-Leucine Zipper Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C117963:NFE2L3 protein, human; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D000521:alpha-MSH