The Role of Endothelin‐1 in Epidermal Hyperpigmentation and Signaling Mechanisms of Mitogenesis and Melanogenesis

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Abstract
The paracrine linkage of endothelins (ET) between keratinocytes and melanocytes suggested that ETs are intrinsic mediators for human melanocytes in UVB‐induced pigmentation. In this study, the role of ET‐1 in the epidermal hyperpigmentation was investigated in vivo and in vitro. The addition of 10 nM ET‐1 induced a H‐7 (10 μM) suppressible‐increase in tyrosinase activity in cultured human melanocytes and was accompanied by elevated levels of tyrosinase and tyrosinase‐related protein‐1 mRNA expression as shown by Northern blotting. Analysis of signaling mechanisms leading to tyrosinase activation demonstrated the involvements of quick translocation of PKC, the H‐7 (10 μM) suppressible‐phosphorylation of the threonine residue of several proteins, and highly elevated level of cyclic AMP (4‐fold over control). Reverse transcription polymerase chain reaction (RT‐PCR) of RNA isolated from the epidermis of human skin exposed to UVB revealed that UVB irradiation with a dose of 2 MED caused a significant increase in the expressions of ET 1, IL‐1α, and tyrosinase mRNA signals 5 days after irradiation. The involvement of ET‐1 in UVB‐pigmentation was also corroborated by the experiments that the extracts of M. Chamomilla, which can act as an antagonist for ET receptor binding‐mediated signaling but has no inhibitory effect on tyrosinase activity in culture, had a significant inhibitory effect on UVB‐induced pigmentation in vivo when daily applied immediately after UVB exposure to human skin. These findings suggest that ET‐1 is an important mediator in the epidermis for UVB‐induced pigmentation in vivo.