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Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model
TNF-α plays a crucial role in psoriasis; therefore, TNF inhibition has become a gold standard for the treatment of psoriasis. TNF-α is processed from a membrane-bound form by TNF-α converting enzyme (TACE) to soluble form, which exerts a number of biological activities. EGF receptor (EGFR) ligands,...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226544/ https://www.ncbi.nlm.nih.gov/pubmed/25384035 http://dx.doi.org/10.1371/journal.pone.0112408 |
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author | Sato, Kenji Takaishi, Mikiro Tokuoka, Shota Sano, Shigetoshi |
author_facet | Sato, Kenji Takaishi, Mikiro Tokuoka, Shota Sano, Shigetoshi |
author_sort | Sato, Kenji |
collection | PubMed |
description | TNF-α plays a crucial role in psoriasis; therefore, TNF inhibition has become a gold standard for the treatment of psoriasis. TNF-α is processed from a membrane-bound form by TNF-α converting enzyme (TACE) to soluble form, which exerts a number of biological activities. EGF receptor (EGFR) ligands, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and transforming growth factor (TGF)-α are also TACE substrates and are psoriasis-associated growth factors. Vascular endothelial growth factor (VEGF), one of the downstream molecules of EGFR and TNF signaling, plays a key role in angiogenesis for developing psoriasis. In the present study, to assess the possible role of TACE in the pathogenesis of psoriasis, we investigated the involvement of TACE in TPA-induced psoriasis-like lesions in K5.Stat3C mice, which represent a mouse model of psoriasis. In this mouse model, TNF-α, amphiregulin, HB-EGF and TGF-α were significantly up-regulated in the skin lesions, similar to human psoriasis. Treatment of K5.Stat3C mice with TNF-α or EGFR inhibitors attenuated the skin lesions, suggesting the roles of TACE substrates in psoriasis. Furthermore, the skin lesions of K5.Stat3C mice showed down-regulation of tissue inhibitor of metalloproteinase-3, an endogenous inhibitor of TACE, and an increase in soluble TNF-α. A TACE inhibitor abrogated EGFR ligand-dependent keratinocyte proliferation and VEGF production in vitro, suggesting that TACE was involved in both epidermal hyperplasia and angiogenesis during psoriasis development. These results strongly suggest that TACE contributes to the development of psoriatic lesions through releasing two kinds of psoriasis mediators, TNF-α and EGFR ligands. Therefore, TACE could be a potential therapeutic target for the treatment of psoriasis. |
format | Online Article Text |
id | pubmed-4226544 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42265442014-11-13 Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model Sato, Kenji Takaishi, Mikiro Tokuoka, Shota Sano, Shigetoshi PLoS One Research Article TNF-α plays a crucial role in psoriasis; therefore, TNF inhibition has become a gold standard for the treatment of psoriasis. TNF-α is processed from a membrane-bound form by TNF-α converting enzyme (TACE) to soluble form, which exerts a number of biological activities. EGF receptor (EGFR) ligands, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and transforming growth factor (TGF)-α are also TACE substrates and are psoriasis-associated growth factors. Vascular endothelial growth factor (VEGF), one of the downstream molecules of EGFR and TNF signaling, plays a key role in angiogenesis for developing psoriasis. In the present study, to assess the possible role of TACE in the pathogenesis of psoriasis, we investigated the involvement of TACE in TPA-induced psoriasis-like lesions in K5.Stat3C mice, which represent a mouse model of psoriasis. In this mouse model, TNF-α, amphiregulin, HB-EGF and TGF-α were significantly up-regulated in the skin lesions, similar to human psoriasis. Treatment of K5.Stat3C mice with TNF-α or EGFR inhibitors attenuated the skin lesions, suggesting the roles of TACE substrates in psoriasis. Furthermore, the skin lesions of K5.Stat3C mice showed down-regulation of tissue inhibitor of metalloproteinase-3, an endogenous inhibitor of TACE, and an increase in soluble TNF-α. A TACE inhibitor abrogated EGFR ligand-dependent keratinocyte proliferation and VEGF production in vitro, suggesting that TACE was involved in both epidermal hyperplasia and angiogenesis during psoriasis development. These results strongly suggest that TACE contributes to the development of psoriatic lesions through releasing two kinds of psoriasis mediators, TNF-α and EGFR ligands. Therefore, TACE could be a potential therapeutic target for the treatment of psoriasis. Public Library of Science 2014-11-10 /pmc/articles/PMC4226544/ /pubmed/25384035 http://dx.doi.org/10.1371/journal.pone.0112408 Text en © 2014 Sato et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sato, Kenji Takaishi, Mikiro Tokuoka, Shota Sano, Shigetoshi Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model |
title | Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model |
title_full | Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model |
title_fullStr | Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model |
title_full_unstemmed | Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model |
title_short | Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model |
title_sort | involvement of tnf-α converting enzyme in the development of psoriasis-like lesions in a mouse model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226544/ https://www.ncbi.nlm.nih.gov/pubmed/25384035 http://dx.doi.org/10.1371/journal.pone.0112408 |
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