Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways

Zorica Janjetovic,Cory Duprey,Russel J Reiter,Andrzej T Slominski,Stuart G Jarrett,Elizabeth F Lee

doi:10.1038/s41598-017-01305-2

Abstract

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing of NRF2 using siRNA diminished the protective effects of melatonin, while the membrane melatonin receptors (MT1 or MT2) did not change the activities of either melatonin or its derivatives. Melatonin and its metabolites enhanced the DNA repair in melanocytes exposed to UVB and stimulated expression of p53 phosphorylated at Ser-15. In conclusion, melatonin and its metabolites protect melanocytes from UVB-induced DNA damage and oxidative stress through activation of NRF2-dependent pathways; these actions are independent of an effect on the classic membrane melatonin receptors. Thus, melatonin and its derivatives can serve as excellent protectors of melanocytes against UVB-induced pathology.

Highlights

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells
Since it was proposed that nuclear factor erythroid 2 –like 2 (NRF2) acts as a master regulator of antioxidative responses and protection against UV6, we investigated whether protective effects of melatonin and its metabolites in human melanocytes are mediated through activation of NRF2
We assessed the protection from oxidative stress and antioxidative defence mechanisms in cells treated with melatonin or its metabolites that were irradiated with UVB intensities of 25 or 50 mJ/cm[2]; this dose does not significantly affect the survival of melanocytes[34]

Summary

Introduction

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Melatonin and its metabolites protect melanocytes from UVB-induced DNA damage and oxidative stress through activation of NRF2-dependent pathways; these actions are independent of an effect on the classic membrane melatonin receptors. Exposure of the skin to ultraviolet radiation (UVR), especially UVB (290–320 nm), absorbed mainly in the epidermis, induces direct DNA damage[1] as cyclobutane pyrimidine dimers (CPD) and pyrimidine photoproducts (6–4)PPs2, 3 with additional production of reactive oxygen species (ROS)[4]. These changes have detrimental effects that include carcinogenesis, cell senescence and other skin pathologies. Melatonin metabolites include 6-Hydroxymelatonin (6-OHM) and 5-methoxytryptamine (5-MT) produced via classical or indolic pathway, respectively[11]

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Conclusion