Melatonin Regulates Arylhydrocarbon Receptor Mediated UVR‐Induced Processes Related to Inflammation, Skin Aging and Carcinogenesis in Human Ex Vivo Skin

ABSTRACT UV radiation (UVR), a known skin‐stressor causing inflammation, aging and carcinogenesis, activates the arylhydrocarbon receptor (AhR) and downstream molecules which are crucially involved in photo‐induced skin damage. In this study, the potent UV protector melatonin was investigated regarding UVR‐mediated activation of AhR and downstream molecules including tumor suppressor p27, DNA double‐strand break marker pH2AX, cyclooxygenase‐2 (COX‐2), mitogen‐activated protein kinase‐14 (MAPK14)/p38α, matrix metalloproteinase‐2 (MMP2) and tissue inhibitor of matrix metalloproteinase‐1 (TIMP1). They were studied in ex vivo human full‐thickness skin irradiated with UVA/B light (0, 300 mJ/cm 2 ) 0 h and 24 h post UV exposure, comparing skin pre‐incubated with or without melatonin. Protein expression was analysed by immunofluorescence staining, gene expression by real‐time qPCR. UV exposure significantly up‐regulated AhR ( p < 0.0001), p27 ( p < 0.001) and pH2AX ( p < 0.0001) protein expression 0 h and 24 h post‐irradiation which was significantly counteracted by melatonin (10 −3 M) at both time points. Further, melatonin significantly reduced gene expression of AhR by 21.2% ( p < 0.01), p27 by 24.8% ( p < 0.01), COX‐2 by 42.9% ( p < 0.001), MAPK14 by 6.6% ( p < 0.05) and MMP2 by 8.2% ( p < 0.05), and caused a 10.2% (n.s.) TIMP1 reduction tendency 24 h post‐irradiation. Thus, melatonin prevented UV‐dependent expression of AhR and downstream regulators of AhR‐mediated processes possibly related to inflammation, cellular aging and carcinogenesis on protein and gene level in UV‐irradiated skin.