Skin
hyperpigmentation is characterized by increased
melanin synthesis and deposition that can cause significant psychosocial and psychological distress. Although several
cytokine-receptor signaling cascades contribute to the formation of ultraviolet B-induced cutaneous
hyperpigmentation, their possible involvement in other types of skin
hyperpigmentation has never been clearly addressed. Since our continuous studies using skin specimens from more than 30 subjects with ethnic skin diversity emphasized a consistent augmentation in the expression of
endothelin-1 (ET-1) and its
receptor (Endothelin B receptor, ET-B) in hyperpigmented lesions, including senile
lentigos (SLs), the precise function of ET-1 signaling was investigated in the present study. In line with previous studies, ET-1 significantly induced melanogenesis followed by increases in melanosome transport in melanocytes and in its transfer to keratinocytes while inhibition of ET-B function substantially depressed melanogenic ability in tissue-cultured SLs. Additionally, in agreement with a previous report that the formation of autophagosomes rather than melanosomes is stimulated according to
starvation or defective melanosome production, ET-1 was found to remarkably augment the expression of components necessary for early melanosome formation, indicating its counteraction against autophagy-targeting melanosome degradation in melanocytes. Despite the lack of substantial impact of ET-1 on keratinocyte melanogenic functions, the expression of ET-1 was enhanced following melanosome uptake by keratinocytes. Taken together, our data suggest that ET-1 plays a substantial role in the development and/or maintenance of skin
hyperpigmentation in reciprocal cooperation with increased melanosome incorporation.