endothelin-1 and Keratosis--Seborrheic

We previously reported that increased expression of the endothelin (EDN)1/EDNB receptor (EDNBR) as well as the stem cell factor (SCF)/SCF receptor (c-KIT) linkages is mainly responsible for the activation of melanocytes in the epidermal hyperpigmentation of ultraviolet (UV)-B melanosis and lentigo senilis (LS). In this study, we characterized seborrheic keratosis (SK) to examine the paracrine cytokine mechanism(s) involved in its epidermal hyperpigmentation by reverse transcription polymerase chain reaction, immunohistochemistry and western blotting analyses. In contrast to our previous study which showed the upregulated expression of EDN1 and EDNBR at the transcriptional and translational levels in the epidermis of SK, we observed unexpectedly that the cytokine SCF and its receptor c-KIT are not upregulated, but are downregulated at both the gene and protein levels. We established SK cell lines to examine whether SK basaloid cells are less sensitive to SCF-inducible stimulation than are normal human keratinocytes (NHK). Comparison of the stimulatory effects of interleukin (IL)-1α or tumor necrosis factor (TNF)-α on SCF production between SK cells and NHK demonstrated that SK cells do not respond to IL-1α or TNF-α to stimulate production of SCF, whereas a significant stimulation of SCF is elicited by those same cytokines in NHK. These finding underscore a role of phenotypic changes in melanogenic cytokine production in the epidermis between SK and LS/UV-B melanosis.

Topics: Adult; Aged; Aged, 80 and over; alpha-MSH; Cells, Cultured; Down-Regulation; Endothelin-1; Female; Humans; Hyperpigmentation; Immunohistochemistry; Keratosis, Seborrheic; Male; Middle Aged; Paracrine Communication; Proto-Oncogene Proteins c-kit; Skin; Stem Cell Factor; Up-Regulation

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

Topics: Cell Culture Techniques; Endothelin-1; Gene Expression; Humans; Hyperpigmentation; Immunoenzyme Techniques; Keratinocytes; Keratosis, Seborrheic; Metalloendopeptidases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Seborrhoeic keratosis (SK) is a benign epidermal tumour with a varying degree of pigmentation. We have recently demonstrated that endothelin-1 (ET-1) is a strong keratinocyte-derived mitogen and melanogen for human melanocytes in UVB-induced melanosis. To clarify the role of ET-1 in hyperpigmentation in SK, we have used immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to see whether the production of ET-1 is accentuated in SK. Immunohistochemical analysis in SK (n = 7; acanthotic and deeply pigmented types) revealed marked immunostaining with anti-ET-1 in almost all basaloid and basal cells as compared with definite staining confined to basal cells in the perilesional normal controls. In parallel, RT-PCR of ET-1 mRNA demonstrated accentuated expression of ET-1 transcript in SK (n = 4) in comparison with that in the perilesional normal controls, accompanied by a similarly accentuated expression of tyrosinase mRNA. These findings suggest that ET-1 plays a part in the hyperpigmentation seen in SK.

Topics: Adult; Aged; Endothelin-1; Female; Humans; Hyperpigmentation; Immunohistochemistry; Keratinocytes; Keratosis, Seborrheic; Male; Middle Aged; Monophenol Monooxygenase; Polymerase Chain Reaction; RNA, Messenger