Little is known about the mechanism(s) underlying
hyperpigmentation in
lentigo senilis. We have previously reported that keratinocyte-derived
endothelins are intrinsic paracrine
mitogens and melanogens for human melanocytes and that they play an essential role in stimulating ultraviolet-B-induced melanogenesis. In this study, we have used immunohistochemistry and
reverse transcriptase polymerase chain reaction analysis to clarify the role of the
endothelin cascade, including
endothelin production, processing by
endothelin-converting enzyme, and expression of the
endothelin B receptor, in the hyperpigmentary mechanism(s) involved in
lentigo senilis. The number of
tyrosinase immunopositive melanocytes in
lentigo senilis lesional skin was increased 2-fold over the perilesional epidermis. Immunohistochemistry using
antibodies to
endothelin-1 demonstrated relatively stronger staining in the lesional epidermis than in the perilesional epidermis.
Reverse transcriptase polymerase chain reaction analysis concomitantly demonstrated accentuated expression of transcripts for
endothelin-1 and for the
endothelin B receptor in
lentigo senilis lesional skin, which was accompanied by a similar accentuated expression of
tyrosinase mRNA compared with the perilesional control. The endothelin-1-inducible
cytokine,
tumor necrosis factor alpha, was consistently upregulated in the
lentigo senilis lesional epidermis as determined at the transcriptional level and by immunostaining, whereas
interleukin-1alpha was downregulated. In contrast,
endothelin-converting enzyme 1alpha
mRNA was not substantially increased in the lesional epidermis. These findings suggest that an accentuation of the epidermal
endothelin cascade, especially with respect to expression of
endothelin and the
endothelin B receptor, plays an important role in the mechanism involved in the
hyperpigmentation of
lentigo senilis.