Abstract
Ultraviolet radiation is a well established epidemiologic risk factor for malignant melanoma. This observation has been linked to the relative resistance of normal melanocytes to ultraviolet B (UVB) radiation-induced apoptosis, which consequently leads to accumulation of UVB radiation-induced DNA lesions in melanocytes. Therefore, identification of physiologic factors regulating UVB radiation-induced apoptosis and DNA damage of melanocytes is of utmost biological importance. We show that the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) blocks UVB radiation-induced apoptosis of normal human melanocytes in vitro. The anti-apoptotic activity of alpha-MSH is not mediated by filtering or by induction of melanin synthesis in melanocytes. alpha-MSH neither leads to changes in the cell cycle distribution nor induces alterations in the expression of the apoptosis-related proteins Bcl(2), Bcl(x), Bax, p53, CD95 (Fas/APO-1), and CD95L (FasL). In contrast, alpha-MSH markedly reduces the formation of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers, ultimately leading to reduced apoptosis. The reduction of UV radiation-induced DNA damage by alpha-MSH appears to be related to induction of nucleotide excision repair, because UV radiation-mediated apoptosis was not blocked by alpha-MSH in nucleotide excision repair-deficient fibroblasts. These data, for the first time, demonstrate regulation of UVB radiation-induced apoptosis of human melanocytes by a neuropeptide that is physiologically expressed within the epidermis. Apart from its ability to induce photoprotective melanin synthesis, alpha-MSH appears to exert the capacity to reduce UV radiation-induced DNA damage and, thus, may act as a potent protection factor against the harmful effects of UV radiation on the genomic stability of epidermal cells.
Highlights
Apoptosis of epidermal cells by ultraviolet B (UVB1; 290 –320 nm) radiation is a well described phenomenon in vitro and in
UVB radiation-induced apoptosis has been recognized as a protective mechanism because it contributes to the elimination of cells carrying DNA damage, thereby preventing malignant transformation [39]
In contrast to NHKs, which are quite prone to apoptosis and appear in situ as sunburn cells, normal human melanocytes (NHMs) have been reported to be quite resistant to UV radiation-induced apoptosis [33]
Summary
Cell Culture—NHMs and human dermal fibroblasts (HDFs) were established from newborn foreskin and purchased from CellSystems Following irradiation with UVB doses ranging from 150 to 400 J/m2, cells were re-stimulated with ␣-MSH in chemically defined medium for an additional 18 h. DNA Content Analysis—NHMs were seeded at a density of 1 ϫ 105 cells per milliliter into 6-cm-diameter tissue culture plates in chemically defined medium without BPE. Cells were subsequently maintained in the presence or absence of ␣-MSH for an additional 18 h followed by determination of mononucleosomes and oligonucleosomes using a death detection ELISA. D and E, suppression of UVB radiation-induced apoptosis of NHMs (D) and NHKs (E) by ␣-MSH as shown by annexin V staining. Data were subsequently analyzed by the Student’s t test
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