Paracrine cytokine mechanisms underlying the hyperpigmentation of seborrheic keratosis in covered skin areas

Takenaka, Yuko; Hoshino, Yumi; Nakajima, Hiroaki; Hayashi, Nobuyuki; Kawashima, Makoto; Imokawa, Genji

doi:10.1111/1346-8138.12178

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…Several cytokines and growth factors, such as ET-1, αMSH and SCF, which are secreted from keratinocytes, can induce the migration, proliferation and melanogenesis of melanocytes, and the increased secretion of these factors is involved in the hyperpigmentation in lentigo seniles and other pigmentation-associated disorders (14,15). To assess the roles of ET-1, αMSH and SCF in the pathogenesis of lentigines in LS, immunohistochemical staining of lesional and non-lesional skin was performed.…”

Section: Immunohistochemical Analysis Of Lentiginesmentioning

confidence: 99%

Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation

Motegi¹,

Yokoyama²,

Ogino³

et al. 2015

Acta Derm Venerol

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LEOPARD syndrome (LS) is an autosomal dominant condition with multiple anomalies, including multiple lentigines. LS is caused by mutations in PTPN11, encoding the protein tyrosine phosphatase, SHP-2. We report here 2 unrelated Japanese cases of LS with different PTPN11 mutations (p.Y279C and p.T468P). To elucidate the pathogenesis of multiple lentigines in LS, ultrastructural and immunohistochemical analyses of lentigines and non-lesional skin were performed. Numerous mature giant melanosomes in melanocytes and keratinocytes were observed in lentigines. In addition, the levels of expression of endothelin-1 (ET-1), phosphorylated Akt, mTOR and STAT3 in the epidermis in lentigines were significantly elevated compared with non-lesional skin. In in vitro assays, melanin synthesis in human melanoma cells expressing SHP-2 with LS-associated mutations was higher than in cells expressing normal SHP-2, suggesting that LS-associated SHP-2 mutations might enhance melanin synthesis in melanocytes, and that the activation of Akt/mTOR signalling may contribute to this process.

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Section: Immunohistochemical Analysis Of Lentiginesmentioning

confidence: 99%

Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation

Motegi¹,

Yokoyama²,

Ogino³

et al. 2015

Acta Derm Venerol

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“…2B - 2D ), supporting the idea that upregulation of bFGF and SCF may be associated with melanogenesis in GDA-overexpressing keratinocytes. Previously, keratinocyte-derived paracrine factors have been reported in connection with seborrheic keratosis or GDA upregulation; increased levels of ET-1 and endothelin B receptor have been considered as potential mechanisms of hyperpigmentation in seborrheic keratosis ( Manaka et al ., 2001 ; Takenaka et al ., 2013 ). Skin pigmentation caused by UV exposure and chronological aging can be regulated by p53 ( Box and Terzian, 2008 ; Yardman-Frank and Fisher, 2021 ; Hoyos et al ., 2022 ) via melanogenic cytokines, such as SCF and ET-1 ( Murase et al ., 2009 ; Hyter et al ., 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…As a mechanism for UV-induced melanogenesis, paracrine factors derived from keratinocytes have been established (López et al, 2015;Swope et al, 2020;Takano et al, 2020). Increased levels of endothelin-1 (ET-1) have also been presented as a potential mechanism of hyperpigmentation in seborrheic keratosis (Takenaka et al, 2013). Roles of uric acid in both melanogenesis and photoaging (Cheong and Lee, 2020;Cheong et al, 2021) cast doubt on uric acid as a common mechanism for UV-induced melanogenesis and photoaghttps://doi.org/10.4062/biomolther.2022.137 ing.…”

Section: Introductionmentioning

confidence: 99%

Growth Factors Upregulated by Uric Acid Affect Guanine Deaminase-Induced Melanogenesis

Kim

Lee

2022

Biomol Ther (Seoul)

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Uric acid produced by guanine deaminase (GDA) is involved in photoaging and hyperpigmentation. Reactive oxygen species (ROS) generated by uric acid plays a role in photoaging. However, the mechanism by which uric acid stimulates melanogenesis in GDA-overexpressing keratinocytes is unclear. Keratinocyte-derived paracrine factors have been identified as important mechanisms of ultraviolet-induced melanogenesis. Therefore, the role of paracrine melanogenic growth factors in GDA-induced hypermelanosis mediated by uric acid was examined. The relationships between ROS and these growth factors were examined. Primary cultured normal keratinocytes overexpressed with wild type or mutant GDA and those treated with xanthine or uric acid in the presence or absence of allopurinol, H2O2, or N-acetylcysteine (NAC) were used in this study. Intracellular and extracellular bFGF and SCF levels were increased in keratinocytes by wild type, but not by loss-of-function mutants of GDA overexpression. Culture supernatants from GDA-overexpressing keratinocytes stimulated melanogenesis, which was restored by anti-bFGF and anti-SCF antibodies. Allopurinol treatment reduced the expression levels of bFGF and SCF in both GDA-overexpressing and normal keratinocytes exposed to exogenous xanthine; the exogenous uric acid increased their expression levels. H2O2-stimulated tyrosinase expression and melanogenesis were restored by NAC pretreatment. However, H2O2 or NAC did not upregulate or downregulate bFGF or SCF, respectively. Overall, uric acid could be involved in melanogenesis induced by GDA overexpression in keratinocytes via bFGF and SCF upregulation not via ROS generation.

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“…This novel mechanism suggests that immune components involved in inflammatory dermatoses may also play a role in SK pathogenesis. Another study found that while the paracrine cytokine SCF and its receptor c-KIT are surprisingly downregulated in SK, high levels of EDN-1 in lesional skin can be attributed to markedly upregulated secretion of EDN-1 production-inducing cytokine TNF-α [63,64]. EDN-1 is a keratinocyte-derived mitogen and strong melanogen in human skin cells [64].…”

Section: Risk Factorsmentioning

confidence: 99%

Advances in the Etiology, Detection, and Clinical Management of Seborrheic Keratoses

Sun

Halpern

2021

Dermatology

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Seborrheic keratoses (SKs) are ubiquitous, generally benign skin tumors that exhibit high clinical variability. While age is a known risk factor, the precise roles of UV exposure and immune abnormalities are currently unclear. The underlying mechanisms of this benign disorder are paradoxically driven by oncogenic mutations and may have profound implications for our understanding of the malignant state. Advances in molecular pathogenesis suggest that inhibition of Akt and APP, as well as existing treatments for skin cancer, may have therapeutic potential in SK. Dermoscopic criteria have also become increasingly important to the accurate detection of SK, and other noninvasive diagnostic methods, such as reflectance confocal microscopy and optical coherence tomography, are rapidly developing. Given their ability to mimic malignant tumors, SK cases are often used to train artificial intelligence-based algorithms in the computerized detection of skin disease. These technologies are becoming increasingly accurate and have the potential to significantly augment clinical practice. Current treatment options for SK cause discomfort and can lead to adverse post-treatment effects, especially in skin of color. In light of the discontinuation of ESKATA in late 2019, promising alternatives, such as nitric-zinc and trichloroacetic acid topicals, should be further developed. There is also a need for larger, head-to-head trials of emerging laser therapies to ensure that future treatment standards address diverse patient needs.

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Paracrine cytokine mechanisms underlying the hyperpigmentation of seborrheic keratosis in covered skin areas

Cited by 8 publications

References 20 publications

Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation

Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation

Growth Factors Upregulated by Uric Acid Affect Guanine Deaminase-Induced Melanogenesis

Advances in the Etiology, Detection, and Clinical Management of Seborrheic Keratoses

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