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Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease

Previous studies have reported the up-regulation of the two-pore domain K(+) channel K(2P)5.1 in the CD4(+) T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regu...

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Autores principales: Endo, Kyoko, Kito, Hiroaki, Tanaka, Ryo, Kajikuri, Junko, Tanaka, Satoshi, Elboray, Elghareeb E., Suzuki, Takayoshi, Ohya, Susumu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981474/
https://www.ncbi.nlm.nih.gov/pubmed/31861667
http://dx.doi.org/10.3390/ijms21010038
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author Endo, Kyoko
Kito, Hiroaki
Tanaka, Ryo
Kajikuri, Junko
Tanaka, Satoshi
Elboray, Elghareeb E.
Suzuki, Takayoshi
Ohya, Susumu
author_facet Endo, Kyoko
Kito, Hiroaki
Tanaka, Ryo
Kajikuri, Junko
Tanaka, Satoshi
Elboray, Elghareeb E.
Suzuki, Takayoshi
Ohya, Susumu
author_sort Endo, Kyoko
collection PubMed
description Previous studies have reported the up-regulation of the two-pore domain K(+) channel K(2P)5.1 in the CD4(+) T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regulation remain unclear. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, such as IBD, MS, and RA, and T cells are exposed to a hypoxic environment during their recruitment from inflamed tissues to secondary lymphoid tissues. We herein investigated whether inflammation-associated hypoxia is attributable to the increased expression and activity of K(2P)5.1 in the splenic CD4(+) T cells of chemically-induced IBD model mice. Significant increases in hypoxia-inducible factor (HIF)-1α transcripts and proteins were found in the splenic CD4(+) T cells of the IBD model. In the activated splenic CD4(+) T cells, hypoxia (1.5% O(2)) increased K(2P)5.1 expression and activity, whereas a treatment with the HIF inhibitor FM19G11 but not the selective HIF-2 inhibitor exerted the opposite effect. Hypoxia-exposed K(2P)5.1 up-regulation was also detected in stimulated thymocytes and the mouse T-cell line. The class III histone deacetylase sirtuin-1 (SIRT1) is a downstream molecule of HIF-1α signaling. We examined the effects of the SIRT1 inhibitor NCO-01 on K(2P)5.1 transcription in activated CD4(+) T cells, and we found no significant effects on the K(2P)5.1 transcription. No acute compensatory responses of K(2P)3.1–K(2P)5.1 up-regulation were found in the CD4(+) T cells of the IBD model and the hypoxia-exposed T cells. Collectively, these results suggest a mechanism for K(2P)5.1 up-regulation via HIF-1 in the CD4(+) T cells of the IBD model.
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spelling pubmed-69814742020-02-07 Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease Endo, Kyoko Kito, Hiroaki Tanaka, Ryo Kajikuri, Junko Tanaka, Satoshi Elboray, Elghareeb E. Suzuki, Takayoshi Ohya, Susumu Int J Mol Sci Article Previous studies have reported the up-regulation of the two-pore domain K(+) channel K(2P)5.1 in the CD4(+) T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regulation remain unclear. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, such as IBD, MS, and RA, and T cells are exposed to a hypoxic environment during their recruitment from inflamed tissues to secondary lymphoid tissues. We herein investigated whether inflammation-associated hypoxia is attributable to the increased expression and activity of K(2P)5.1 in the splenic CD4(+) T cells of chemically-induced IBD model mice. Significant increases in hypoxia-inducible factor (HIF)-1α transcripts and proteins were found in the splenic CD4(+) T cells of the IBD model. In the activated splenic CD4(+) T cells, hypoxia (1.5% O(2)) increased K(2P)5.1 expression and activity, whereas a treatment with the HIF inhibitor FM19G11 but not the selective HIF-2 inhibitor exerted the opposite effect. Hypoxia-exposed K(2P)5.1 up-regulation was also detected in stimulated thymocytes and the mouse T-cell line. The class III histone deacetylase sirtuin-1 (SIRT1) is a downstream molecule of HIF-1α signaling. We examined the effects of the SIRT1 inhibitor NCO-01 on K(2P)5.1 transcription in activated CD4(+) T cells, and we found no significant effects on the K(2P)5.1 transcription. No acute compensatory responses of K(2P)3.1–K(2P)5.1 up-regulation were found in the CD4(+) T cells of the IBD model and the hypoxia-exposed T cells. Collectively, these results suggest a mechanism for K(2P)5.1 up-regulation via HIF-1 in the CD4(+) T cells of the IBD model. MDPI 2019-12-19 /pmc/articles/PMC6981474/ /pubmed/31861667 http://dx.doi.org/10.3390/ijms21010038 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Endo, Kyoko
Kito, Hiroaki
Tanaka, Ryo
Kajikuri, Junko
Tanaka, Satoshi
Elboray, Elghareeb E.
Suzuki, Takayoshi
Ohya, Susumu
Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease
title Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease
title_full Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease
title_fullStr Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease
title_full_unstemmed Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease
title_short Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease
title_sort possible contribution of inflammation-associated hypoxia to increased k(2p)5.1 k(+) channel expression in cd4(+) t cells of the mouse model for inflammatory bowel disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981474/
https://www.ncbi.nlm.nih.gov/pubmed/31861667
http://dx.doi.org/10.3390/ijms21010038
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