Thyrotropin-Releasing Hormone Selectively Stimulates Human Hair Follicle Pigmentation

Abstract

In amphibians, thyrotropin-releasing hormone (TRH) stimulates skin melanophores by inducing secretion of α-melanocyte-stimulating hormone in the pituitary gland. However, it is unknown whether this tripeptide neurohormone exerts any direct effects on pigment cells, namely, on human melanocytes, under physiological conditions. Therefore, we have investigated whether TRH stimulates pigment production in organ-cultured human hair follicles (HFs), the epithelium of which expresses both TRH and its receptor, and/or in full-thickness human skin in situ. TRH stimulated melanin synthesis, tyrosinase transcription and activity, melanosome formation, melanocyte dendricity, gp100 immunoreactivity, and microphthalmia-associated transcription factor expression in human HFs in a pituitary gland-independent manner. TRH also stimulated proliferation, gp100 expression, tyrosinase activity, and dendricity of isolated human HF melanocytes. However, intraepidermal melanogenesis was unaffected. As TRH upregulated the intrafollicular production of "pituitary" neurohormones (proopiomelanocortin transcription and ACTH immunoreactivity) and as agouti-signaling protein counteracted TRH-induced HF pigmentation, these pigmentary TRH effects may be mediated in part by locally generated melanocortins and/or by MC-1 signaling. Our study introduces TRH as a novel, potent, selective, and evolutionarily highly conserved neuroendocrine factor controlling human pigmentation in situ. This physiologically relevant and melanocyte sub-population-specific neuroendocrine control of human pigmentation deserves clinical exploration, e.g., for preventing or reversing hair graying.

Introduction

“…TRH stimulated hair shaft formation, prevented apoptosis, increased proliferation of hair matrix keratinocytes and prolonged the anagen phase of hair growth cycle (Gaspar et al, 2010, van Beek et al, 2008). TRH can also stimulate hair follicle pigmentation (Gaspar et al, 2011), probably by direct activation of melanocortin type 1 receptor (MC-1R), confirming our previous hypothesis (Slominski et al, 2005b, Slominski et al, 2002e). It was shown that TSH acting via TSH-R1 receptor increased cAMP production by human keratinocytes, human and hamster melanoma cells ((Slominski et al, 2002e) and enhanced the proliferation of epidermal keratinocytes and dermal fibroblasts (Bodo at al., 2010).…”

The Peripheral Clock Regulates Human Pigmentation

“…Silencing of core clock components PER1 or BMAL1 increases melanin content in human anagen VI HFs in a hair cycle-independent manner Previously, we had observed that clock gene silencing appeared to increase the melanin content of human HFs (Al-Nuaimi et al, 2014). Therefore, utilizing Masson-Fontana histochemistry for visualizing melanin in BMAL1 or PER1 knock-down HFs we analyzed whether the increase in pigmentation simply reflects the anagen-prolonging effects of gene silencing (Kloepper et al, 2010;Gáspár et al, 2011;Samuelov et al, 2013;Al-Nuaimi et al, 2014).…”

Commentary from the Editorial Board to Vitiligo: interplay between oxidative stress and immune system (Laddha et al.)

“…Thus, environmental endocrine disruptors may likewise target the cutaneous neuroendocrine network and not only classical endocrine organs. With regard to the most commonly associated autoimmune disease of vitiligo, thyroid disease, it is intriguing that the majority of hypothalamic‐pituitary‐thyroid axis related genes are autonomously expressed in human skin with some of the them even directly controlling melanin biosynthesis . Furthermore, the adverse effect of ROS accumulation on autoimmunity might be increased by the potential immunotoxic effect that some environmental pollutants and chemical agents have .…”