Regulation of the Human Melanocortin 1 Receptor Expression in Epidermal Melanocytes by Paracrine and Endocrine Factors and by Ultraviolet Radiation

Abstract

The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R) expression in cultured normal human melanocytes (NHM) by specific paracrine and endocrine factors, and by ultraviolet radiation (UVR). Treatment of NHM with alpha-melanotropin [alpha-melanocyte stimulating hormone (alpha-MSH)] increased MC1R mRNA level; the response was often more pronounced in NHM with a low (NHM-c) than in NHM with a high melanin content (NHM-b). Endothelin-1 increased MC1R mRNA level in NHM regardless of their melanin content. Basic fibroblast growth factor consistently up regulated MC1R mRNA level in NHM-b but not in NHM-c. Activation of protein kinase C by 12-0-tetradecanoylphorbol-13-acetate slightly increased, while stimulation of adenylate cyclase by forskolin markedly up-regulated the MC1R mRNA level. beta-Estradiol increased, and combined treatment with beta-estradiol and alpha-MSH further elevated, MC1R mRNA level in NHM-c and NHM-b. Testosterone reduced, while progesterone had no effect on, MC1R mRNA level. Agouti signaling protein reduced, and UVR down regulated dose-dependently MC1R mRNA level in NHM-b and NHM-c. This effect was reversed 24 h after irradiation with the lower doses of 7 or 14 mJ/cm2, but not after exposure to a higher, more cytotoxic dose of UVR. We conclude that the MC1R is regulated by paracrine factors, including its own ligands, by specific endocrine sex hormones, and by UVR. Differences in the responses of NHM to some of these factors suggest differential regulation of MC1R gene expression, which may contribute to the variation in constitutive and UV-induced cutaneous pigmentation in humans.

Fisiopatologia do melasma

“…Se o MC1-R está envolvido em outras vias sinalizadoras, ainda permanece desconhecido, mas a ativação do MC1-R influencia as quantidades relativas de feomelanina e eumelanina produzidas, sendo sua perda de atividade, associada a cabelos vermelhos ou amarelos. 20,34,38,39,[48][49][50][51][52] Variantes do MC1-R têm sido associadas com a herança de cabelo vermelho, na qual mais pigmento amarelo-avermelhado de feomelanina é produzido e apresentam capacidade de bronzeamento muito pequena. Variantes R160W, R151C, D294H, R142H, 86insA e 537insC de MC1-R são os principais determinantes do fenótipo de cabelos vermelhos e pele clara.…”

“…51 Além disso, em estudo recente demonstrou-se uma expressão aumentada de receptores estrogênicos na pele com melasma, comparada à pele normal, porém a avaliação foi de apenas dois pacientes e de forma qualitativa, o que não permite ainda determinar a real função deste receptor e do estrogênio na fisiopatogenia do melasma. 82 …”

Seeing the gene therapy: application of gene gun technique to transfect and decolour pigmented rat skin with human agouti signalling protein cDNA

“…Most studies have proposed that ASP acts as an antagonist of MC1R, causing MC1R desensitization and consequent reduction of tyrosinase activity. 4,17 However, Scott et al 18 observed that ASP plays a role in the regulation of skin pigmentation through downregulation of MC1R mRNA transcription in cultured human melanocytes. Recently, microphthalmia transcription factor (MITF), which belong to the basic helix-loop-helix family, was found to regulate the gene for MC1R through its promoter region in cultured cells.…”

Solar radiation and human health

“…UV also induces melanin stimulating hormone locally from keratinocytes; such paracrine secretion plays a critical role in local cell regulation from an immunosuppressive and proinflammatory point of view [281,321]. The receptor for pigment regulation within melanocytes, melanocortin receptor, is also regulated by UV [281,322]. 31 The mechanisms underlying immune responsiveness following UV have earlier been reviewed [323].…”