ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.

In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p...

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Autores principales:	Terufumi Kubo, Ryuta Kamekura, Ayako Kumagai, Koji Kawata, Keiji Yamashita, Yukari Mitsuhashi, Takashi Kojima, Kotaro Sugimoto, Akihiro Yoneta, Yasuyuki Sumikawa, Toshiharu Yamashita, Noriyuki Sato, Tetsuo Himi, Shingo Ichimiya
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/254e4f2867714562b30e37d5e7654a04
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spelling	oai:doaj.org-article:254e4f2867714562b30e37d5e7654a042021-11-25T06:02:40ZΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.1932-620310.1371/journal.pone.0105498https://doaj.org/article/254e4f2867714562b30e37d5e7654a042014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25171086/?tool=EBIhttps://doaj.org/toc/1932-6203In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63(lo/-)). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.Terufumi KuboRyuta KamekuraAyako KumagaiKoji KawataKeiji YamashitaYukari MitsuhashiTakashi KojimaKotaro SugimotoAkihiro YonetaYasuyuki SumikawaToshiharu YamashitaNoriyuki SatoTetsuo HimiShingo IchimiyaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e105498 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Terufumi Kubo Ryuta Kamekura Ayako Kumagai Koji Kawata Keiji Yamashita Yukari Mitsuhashi Takashi Kojima Kotaro Sugimoto Akihiro Yoneta Yasuyuki Sumikawa Toshiharu Yamashita Noriyuki Sato Tetsuo Himi Shingo Ichimiya ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
description	In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63(lo/-)). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.
format	article
author	Terufumi Kubo Ryuta Kamekura Ayako Kumagai Koji Kawata Keiji Yamashita Yukari Mitsuhashi Takashi Kojima Kotaro Sugimoto Akihiro Yoneta Yasuyuki Sumikawa Toshiharu Yamashita Noriyuki Sato Tetsuo Himi Shingo Ichimiya
author_facet	Terufumi Kubo Ryuta Kamekura Ayako Kumagai Koji Kawata Keiji Yamashita Yukari Mitsuhashi Takashi Kojima Kotaro Sugimoto Akihiro Yoneta Yasuyuki Sumikawa Toshiharu Yamashita Noriyuki Sato Tetsuo Himi Shingo Ichimiya
author_sort	Terufumi Kubo
title	ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
title_short	ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
title_full	ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
title_fullStr	ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
title_full_unstemmed	ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
title_sort	δnp63 controls a tlr3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/254e4f2867714562b30e37d5e7654a04
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ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.

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