Cargando…

IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis

BACKGROUND: Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53‐like transcription factor, is a...

Descripción completa

Detalles Bibliográficos
Autores principales: Kubo, Terufumi, Sato, Sayuri, Hida, Tokimasa, Minowa, Tomoyuki, Hirohashi, Yoshihiko, Tsukahara, Tomohide, Kanaseki, Takayuki, Murata, Kenji, Uhara, Hisashi, Torigoe, Toshihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342210/
https://www.ncbi.nlm.nih.gov/pubmed/33792188
http://dx.doi.org/10.1002/iid3.427
_version_ 1783734020734976000
author Kubo, Terufumi
Sato, Sayuri
Hida, Tokimasa
Minowa, Tomoyuki
Hirohashi, Yoshihiko
Tsukahara, Tomohide
Kanaseki, Takayuki
Murata, Kenji
Uhara, Hisashi
Torigoe, Toshihiko
author_facet Kubo, Terufumi
Sato, Sayuri
Hida, Tokimasa
Minowa, Tomoyuki
Hirohashi, Yoshihiko
Tsukahara, Tomohide
Kanaseki, Takayuki
Murata, Kenji
Uhara, Hisashi
Torigoe, Toshihiko
author_sort Kubo, Terufumi
collection PubMed
description BACKGROUND: Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53‐like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified. OBJECTIVE: In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD‐associated molecules regulated by ΔNp63 in keratinocytes. METHODS: The immunohistochemical expression profiles of ΔNp63 and AD‐related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD‐related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method. RESULTS: In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier‐related proteins including filaggrin, caspase‐14, claudin‐1, and claudin‐4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL‐1β and IL‐33, pro‐inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL‐13 exposure increased the thickness of the three‐dimensional culture of keratinocytes. IL‐13 interfered with ΔNp63 downregulation during calcium‐induced keratinocyte differentiation. IL‐13 modulated some barrier‐related and inflammation‐related molecules, which were regulated by ΔNp63. CONCLUSIONS: We have shown that ΔNp63 modulated AD‐related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL‐4/IL‐13. IL‐13–ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation.
format Online
Article
Text
id pubmed-8342210
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-83422102021-08-11 IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis Kubo, Terufumi Sato, Sayuri Hida, Tokimasa Minowa, Tomoyuki Hirohashi, Yoshihiko Tsukahara, Tomohide Kanaseki, Takayuki Murata, Kenji Uhara, Hisashi Torigoe, Toshihiko Immun Inflamm Dis Original Articles BACKGROUND: Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53‐like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified. OBJECTIVE: In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD‐associated molecules regulated by ΔNp63 in keratinocytes. METHODS: The immunohistochemical expression profiles of ΔNp63 and AD‐related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD‐related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method. RESULTS: In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier‐related proteins including filaggrin, caspase‐14, claudin‐1, and claudin‐4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL‐1β and IL‐33, pro‐inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL‐13 exposure increased the thickness of the three‐dimensional culture of keratinocytes. IL‐13 interfered with ΔNp63 downregulation during calcium‐induced keratinocyte differentiation. IL‐13 modulated some barrier‐related and inflammation‐related molecules, which were regulated by ΔNp63. CONCLUSIONS: We have shown that ΔNp63 modulated AD‐related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL‐4/IL‐13. IL‐13–ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation. John Wiley and Sons Inc. 2021-04-01 /pmc/articles/PMC8342210/ /pubmed/33792188 http://dx.doi.org/10.1002/iid3.427 Text en © 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Kubo, Terufumi
Sato, Sayuri
Hida, Tokimasa
Minowa, Tomoyuki
Hirohashi, Yoshihiko
Tsukahara, Tomohide
Kanaseki, Takayuki
Murata, Kenji
Uhara, Hisashi
Torigoe, Toshihiko
IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis
title IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis
title_full IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis
title_fullStr IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis
title_full_unstemmed IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis
title_short IL‐13 modulates ∆Np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis
title_sort il‐13 modulates ∆np63 levels causing altered expression of barrier‐ and inflammation‐related molecules in human keratinocytes: a possible explanation for chronicity of atopic dermatitis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342210/
https://www.ncbi.nlm.nih.gov/pubmed/33792188
http://dx.doi.org/10.1002/iid3.427
work_keys_str_mv AT kuboterufumi il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT satosayuri il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT hidatokimasa il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT minowatomoyuki il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT hirohashiyoshihiko il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT tsukaharatomohide il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT kanasekitakayuki il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT muratakenji il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT uharahisashi il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis
AT torigoetoshihiko il13modulatesnp63levelscausingalteredexpressionofbarrierandinflammationrelatedmoleculesinhumankeratinocytesapossibleexplanationforchronicityofatopicdermatitis