Role of endothelin-1 in hyperpigmentation in seborrhoeic keratosis

Teraki, E.; Tajima, S.; Manaka, Izumi; Kawashima, Makoto; Miyagishi, Makoto; Imokawa, Genji

doi:10.1046/j.1365-2133.1996.d01-1095.x

Cited by 44 publications

(47 citation statements)

References 11 publications

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“…16 Therefore, our result further confirmed this observation in SK. The observation of increased expression ET-1, ET-2, and ETRB by BCC is reported here for the first time.…”

Section: Discussionsupporting

confidence: 93%

“…pigmentation. 16 However, since only about half of the SK and none of the BCCs analyzed in this investigation were pigmented, increased expression of ET pathway genes is not likely to be of major significance in regulating lesional pigmentation. The observation that ET pathway blockade resulted in marked decrease in keratinocyte survival in serum-free medium (see Figure 4) suggests another possible function of activated ET pathways in nonmelanoma skin cancers.…”

Section: Discussionmentioning

confidence: 97%

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Expression of Endothelins and Their Receptors in Nonmelanoma Skin Cancers

Zhang

Tang

et al. 2006

J Cutan Med Surg

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Background: Endothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking. Objectives: This study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes. Methods: Quantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, −2, and −3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time. Results: ET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowen's disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival. Conclusion: The endothelin signaling pathway, especially ET-1, is activated in basoloid keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors.

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“…16 Therefore, our result further confirmed this observation in SK. The observation of increased expression ET-1, ET-2, and ETRB by BCC is reported here for the first time.…”

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 97%

Expression of Endothelins and Their Receptors in Nonmelanoma Skin Cancers

Zhang

Tang

et al. 2006

J Cutan Med Surg

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“…It has been reported that expression of ET-1 23) and its receptors is increased 24) in seborrhoeic keratosis and in senile pigmented freckles. Involvement of a mechanism similar to the UVB-induced activation of melanocytes has been suggested for these pigmentation disorders, and thus treatment with the extract of A. officinalis might also be effective in whitening other than hyperpigmentary conditions associated with ET-1 function.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Mechanism of an Extract of Althaea officinalis L. on Endothelin-1-Induced Melanocyte Activation.

Kobayashi

Hachiya

Ohuchi

et al. 2002

Biological & Pharmaceutical Bulletin

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When the skin is irradiated with UVB light, various cytokines are released, act on normal human melanocytes (NHMC), and induce them to synthesize melanin pigment, to proliferate and to differentiate, which leads to increased pigmentation.1-3) Endothelin-1 (ET-1), 2,4) basic fibroblast growth factor (b-FGF), 5) and a-melanocyte-stimulating hormone, [6][7][8] all of which are produced by normal human keratinocytes (NHKC) and are up-regulated following UVB irradiation, act as mitogens for NHMC. Furthermore, an increase in ET-1 expression 3) in human skin after UVB irradiation has also been reported, and it has been suggested that ET-1 plays an important role in UVB-induced pigmentation. Therefore, we have investigated various botanical extracts that inhibit the ET-1-induced activation of NHMC. Since intracellular calcium mobilization is induced when ET-1 acts on NHMC, 1) we have continued to search for new agents which can block this calcium mobilization and we have found that an extract of Althaea officinalis L. has a potent inhibitory effect. In this study, we have clarified the inhibitory mechanism of the extract of A. officinalis on ET-1-induced activation of NHMC. MATERIALS AND METHODS Extract of A. officinalis L.A. officinalis is a large perennial plant belonging to the genus hollyhock in the mallow family. Pale pink hollyhock, velvet hollyhock, and marshmallow also belong to this family, and A. officinalis is cultivated for gardening, medication, and food in Europe. The genus name 'Althaea' is derived from 'althaino' in Greek, meaning therapy. The species name 'officinalis' means 'use for drug', and the plant is often prescribed for pain relief and treatment of renal function, inflammation, and irritation syndrome. The portions of the plant used as a drug are the roots and leaves that contain abundant mucus. Marshmallow sweet was originally sipped to treat sore throats, and can be jelled by soaking the root powder with sugar in water. We extracted A. officinalis roots with a 45% 1,3-butylene glycol solution and obtained a brown transparent extract, which was used in this evaluation.Materials NHMC were obtained from KURABO Industries, Ltd. (Osaka, Japan) and NHKC were obtained from Sanko Junyaku Co., Ltd. (Tokyo, Japan). Serum-free NHMC medium (MGM) was purchased from Sanko Pure Chemicals (Tokyo, Japan) and serum-free NHKC medium (SFM) and Dulbecco's modified Eagle's medium (DMEM) were purchased from Gibco Laboratories (Grand Island, NY, U.S.A.). ET derivatives were purchased from Wako Pure Chemical Industries, Ltd. (Tokyo, Japan). Other chemicals were of reagent grade.Cell Culture NHMC were maintained in MGM supplemented with 1 ng/ml recombinant b-FGF, 0.5 mg/ml hydrocortisone, 5 mg/ml insulin, 10 ng/ml phorbol 12-myristate 13-acetate, 3 mg/ml heparin, antibiotics (50 mg/ml streptomycin), and 0.2% bovine pituitary extract (BPE). NHKC were maintained in modified SFM supplemented with 5 ng/ml epidermal growth factor and 50 mg/ml BPE. B16 F10 melanoma cells are a subline of the pigmented B16 melanoma (C57BL/6N)...

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“…49,50 Furthermore, type IV Waardenburg syndrome (Shah-Waardenburg syndrome with Hirschsprung disease) is caused by mutations in the genes encoding ET-3 or ET B R. 48 In addition to their significance during the development of melanocytes, ET-1 and/or SCF are involved in melanocyte activation in several human pigmentary disorders such as lentigo senilis, dermatofibroma, café -aulait macules, and seborrehoic keratosis. [51][52][53][54][55] Especially in lentigo senilis, which is similar in histological aspects to UVB-melanosis, the enhanced expression of SCF and ET-1 occurs concomitantly with an increased expression of ET B R in the lesional pigmented epidermis.…”

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confidence: 97%

Biphasic Expression of Two Paracrine Melanogenic Cytokines, Stem Cell Factor and Endothelin-1, in Ultraviolet B-Induced Human Melanogenesis

Hachiya¹,

Kobayashi²,

Yoshida³

et al. 2004

The American Journal of Pathology

107

130

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Stem cell factor (SCF) and endothelin-1 (ET-1) have been reported to be up-regulated at the protein and gene levels in human epidermis after ultraviolet B (UVB) irradiation and to play central roles in UVBinduced pigmentation. However, little is known about the time sequence of SCF and ET-1 expression in UVB-exposed human epidermis and the coordination of their roles during epidermal pigmentation. To clarify such parameters in UVB-exposed human skin, we measured the expression patterns of SCF and ET-1 (as well as of their corresponding receptors) at the gene level at various times during UVB-induced human pigmentation. When human forearm skin was exposed to UVB radiation at two minimal erythemal doses, the expression of SCF mRNA transcripts was significantly enhanced at 3 days after irradiation with an early decrease and subsequently constant expression of SCF receptor (c-KIT) mRNA transcripts. In contrast, up-regulation of ET-1 and endothelin B receptor (ET B R) mRNA expression was synchronized at 5 to 10 days after irradiation in concert with an increased expression of tyrosinase mRNA transcripts and the increase in pigmentation. In parallel the expression of tyrosinase and ET B R proteins as well as ET-1 was up-regulated at 7 to 10 days after irradiation, whereas KIT protein decreased at 3 days after irradiation and returned to the nonirradiated control level at 5 days after irradiation. When cultured human melanocytes were treated with human recombinant SCF, ET B R protein expression and the binding of 125 I-labeled ET-1 to the ET B R were significantly increased, further suggesting the preferential and coordinated role of early expression of SCF in UVB-induced melanogenesis. These findings suggest that SCF/KIT signaling is predominantly involved in the early phase of UVB-induced human pigmentation during which it stimulates the ET-1/ET B R linkage that is associated with the later phase of UVB-induced melanogenesis.

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Role of endothelin-1 in hyperpigmentation in seborrhoeic keratosis

Cited by 44 publications

References 11 publications

Expression of Endothelins and Their Receptors in Nonmelanoma Skin Cancers

Expression of Endothelins and Their Receptors in Nonmelanoma Skin Cancers

Inhibitory Mechanism of an Extract of Althaea officinalis L. on Endothelin-1-Induced Melanocyte Activation.

Biphasic Expression of Two Paracrine Melanogenic Cytokines, Stem Cell Factor and Endothelin-1, in Ultraviolet B-Induced Human Melanogenesis

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