The mechanism of hyperpigmentation in seborrhoeic keratosis involves the high expression of endothelin-converting enzyme-1α and TNF-α, which stimulate secretion of endothelin 1


Genji Imokawa, PhD. E-mail:


Background Seborrhoeic keratosis (SK) is a benign epidermal tumour with increased pigmentation. We have recently demonstrated that increased secretion of endothelin (ET)-1, a strong keratinocyte-derived mitogen and melanogen for human melanocytes, is intrinsically involved in the hyperpigmentation mechanism of SK.

Objectives To examine whether the increased ET secretion results from cytokines that induce ET production and/or from differences in the processing of ET that lead to its final active, secreted form.

Methods We used immunohistochemistry and reverse transcription–polymerase chain reaction (RT–PCR) to determine whether ET-inducing enzymes and/or cytokines are also highly expressed in SK.

Results RT–PCR of mRNAs encoding interleukin (IL)-1α, tumour necrosis factor (TNF)-α and endothelin-converting enzyme (ECE)-1α demonstrated that there is an increased expression of TNF-α and ECE-1α mRNAs in SK, whereas the IL-1α transcript is rather downregulated in SK compared with that in perilesional normal epidermis. In parallel, immunohistochemical analysis of SK revealed marked immunostaining for TNF-α in basaloid cells at lower levels of the epidermis and in basal cells, and for ECE-1α in most basaloid and basal cells in comparison with their weak staining throughout the epidermis in perilesional normal controls. In contrast, immunostaining for IL-1α was almost negative in SK relative to distinctive staining throughout the epidermis in the perilesional normal controls.

Conclusions These findings suggest that the increased secretion of ET-1 leading to enhanced pigmentation in SK results from the co-ordinated increased expression of TNF-α and ECE-1α.