Abstract
The human body follows a physiological rhythm in response to the day/night cycle which is synchronized with the circadian rhythm through internal clocks. Most cells in the human body, including skin cells, express autonomous clocks and the genes responsible for running those clocks. Melatonin, a ubiquitous small molecular weight hormone, is critical in regulating the sleep cycle and other functions in the body. Melatonin is present in the skin and, in this study, we showed that it has the ability to dose-dependently stimulate PER1 clock gene expression in normal human dermal fibroblasts and normal human epidermal keratinocytes. Then we further evaluated the role of MT-1 melatonin receptor in mediating melatonin actions on human skin using fibroblasts derived from young and old subjects. Using immunocytochemistry, Western blotting and RT-PCR, we confirmed the expression of MT-1 receptor in human skin fibroblasts and demonstrated a dramatic age-dependent decrease in its level in mature fibroblasts. We used siRNA technology to transiently knockdown MT-1 receptor in fibroblasts. In these MT-1 knockdown cells, UV-dependent oxidative stress (H2O2 production) was enhanced and DNA damage was also increased, suggesting a critical role of MT-1 receptor in protecting skin cells from UV-induced DNA damage. These studies demonstrate that the melatonin pathway plays a pivotal role in skin aging and damage. Moreover, its correlation with skin circadian rhythm may offer new approaches for decelerating skin aging by modulating the expression of melatonin receptors in human skin.
Highlights
Skin, the largest and the most external organ of the human body, is directly exposed to environmental insults including extreme temperatures, light, humidity, ultraviolet (UV) radiation, air pollution and pathogens
We have previously reported that melatonin increases PER1 levels in normal human keratinocytes, which means that it is directly involved in controlling the circadian rhythm of skin cells [16]
Melatonin has been shown to play a direct role in controlling PER1 clock gene expression and the natural secretion of melatonin follows a circadian rhythm, highest at night and lower during the day
Summary
The largest and the most external organ of the human body, is directly exposed to environmental insults including extreme temperatures, light, humidity, ultraviolet (UV) radiation, air pollution (smog, ozone, particulate pollutants, etc.) and pathogens. The skin is equipped with an elaborate antioxidant system to deal with oxidative stress, chronic exposure to environmental insults, especially UV exposure, can overcome the endogenous antioxidant capacity of the skin and result in cellular damage and skin disease [2,3]. Many of these antioxidants and antioxidant enzyme systems in the skin are reduced with age, making the older skin more vulnerable to environmental insults [4]. The skin produces several protective molecules including melatonin, melanin and vitamin D to counteract oxidative stress [4,5] The production of these molecules might be controlled by a 24 h light/dark cycle. It is clear that all major cell types in the human skin have functional circadian machinery and display specific periods and phase relationships in gene expression, suggesting regulatory mechanisms that are particular to each cell type [12]
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