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Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes
The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the r...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827910/ https://www.ncbi.nlm.nih.gov/pubmed/31682627 http://dx.doi.org/10.1371/journal.pone.0224705 |
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author | Tashiro, Naoyuki Segawa, Ryosuke Tobita, Ryozo Asakawa, Sanki Mizuno, Natsumi Hiratsuka, Masahiro Hirasawa, Noriyasu |
author_facet | Tashiro, Naoyuki Segawa, Ryosuke Tobita, Ryozo Asakawa, Sanki Mizuno, Natsumi Hiratsuka, Masahiro Hirasawa, Noriyasu |
author_sort | Tashiro, Naoyuki |
collection | PubMed |
description | The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O(2)), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl(2), CoCl(2), and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis. |
format | Online Article Text |
id | pubmed-6827910 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-68279102019-11-12 Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes Tashiro, Naoyuki Segawa, Ryosuke Tobita, Ryozo Asakawa, Sanki Mizuno, Natsumi Hiratsuka, Masahiro Hirasawa, Noriyasu PLoS One Research Article The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O(2)), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl(2), CoCl(2), and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis. Public Library of Science 2019-11-04 /pmc/articles/PMC6827910/ /pubmed/31682627 http://dx.doi.org/10.1371/journal.pone.0224705 Text en © 2019 Tashiro 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Tashiro, Naoyuki Segawa, Ryosuke Tobita, Ryozo Asakawa, Sanki Mizuno, Natsumi Hiratsuka, Masahiro Hirasawa, Noriyasu Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes |
title | Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes |
title_full | Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes |
title_fullStr | Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes |
title_full_unstemmed | Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes |
title_short | Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes |
title_sort | hypoxia inhibits tnf-α-induced tslp expression in keratinocytes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827910/ https://www.ncbi.nlm.nih.gov/pubmed/31682627 http://dx.doi.org/10.1371/journal.pone.0224705 |
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