Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis

Immunoparalysis is an important pathological mechanism in sepsis. However, an effective small molecule therapy is lacking. Here, we show that ouabain, a Na(+),K(+)-ATPase ligand, can reverse immunoparalysis in vitro, in vivo, and in clinical samples. Notably, the effect of ouabain was critically dep...

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Autores principales: Dan, Cao, Jinjun, Bian, Zi-Chun, Hua, Lin, Ma, Wei, Chen, Xu, Zhang, Ri, Zhou, Shun, Cheng, Wen-Zhu, Sun, Qing-Cai, Jiao, Wu, Yin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328645/
https://www.ncbi.nlm.nih.gov/pubmed/25535255
http://dx.doi.org/10.15252/emmm.201404797
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author Dan, Cao
Jinjun, Bian
Zi-Chun, Hua
Lin, Ma
Wei, Chen
Xu, Zhang
Ri, Zhou
Shun, Cheng
Wen-Zhu, Sun
Qing-Cai, Jiao
Wu, Yin
author_facet Dan, Cao
Jinjun, Bian
Zi-Chun, Hua
Lin, Ma
Wei, Chen
Xu, Zhang
Ri, Zhou
Shun, Cheng
Wen-Zhu, Sun
Qing-Cai, Jiao
Wu, Yin
author_sort Dan, Cao
collection PubMed
description Immunoparalysis is an important pathological mechanism in sepsis. However, an effective small molecule therapy is lacking. Here, we show that ouabain, a Na(+),K(+)-ATPase ligand, can reverse immunoparalysis in vitro, in vivo, and in clinical samples. Notably, the effect of ouabain was critically dependent on TNF-α expression. However, ouabain had opposing effects on the stability of TNF-α mRNA: Ouabain triggered miR-181 transcription, which promoted TNF-α mRNA degradation and induced immunoparalysis, and ouabain triggered the nuclear export of human antigen R (HuR), which stabilized TNF-α mRNA and suppressed immuno-paralysis. Interestingly, because the miR-181 binding site is located within the HuR binding site in the 3′-untranslated region of TNF-α, in ouabain-treated cells, HuR competed with miR-181 for binding to TNF-α mRNA and recruited TNF-α mRNA to stress granules, thereby stabilizing TNF-α mRNA and reversing immunoparalysis. Ouabain also induced GM-CSF and interferon-γ expression in a HuR-dependent manner. Hence, the fine-tuning of TNF-α mRNA stability by HuR and miR181 plays a crucial role in immunoparalysis, and Na(+),K(+)-ATPase ligands are promising agents for immunoparalysis therapy.
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spelling pubmed-43286452015-02-17 Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis Dan, Cao Jinjun, Bian Zi-Chun, Hua Lin, Ma Wei, Chen Xu, Zhang Ri, Zhou Shun, Cheng Wen-Zhu, Sun Qing-Cai, Jiao Wu, Yin EMBO Mol Med Research Articles Immunoparalysis is an important pathological mechanism in sepsis. However, an effective small molecule therapy is lacking. Here, we show that ouabain, a Na(+),K(+)-ATPase ligand, can reverse immunoparalysis in vitro, in vivo, and in clinical samples. Notably, the effect of ouabain was critically dependent on TNF-α expression. However, ouabain had opposing effects on the stability of TNF-α mRNA: Ouabain triggered miR-181 transcription, which promoted TNF-α mRNA degradation and induced immunoparalysis, and ouabain triggered the nuclear export of human antigen R (HuR), which stabilized TNF-α mRNA and suppressed immuno-paralysis. Interestingly, because the miR-181 binding site is located within the HuR binding site in the 3′-untranslated region of TNF-α, in ouabain-treated cells, HuR competed with miR-181 for binding to TNF-α mRNA and recruited TNF-α mRNA to stress granules, thereby stabilizing TNF-α mRNA and reversing immunoparalysis. Ouabain also induced GM-CSF and interferon-γ expression in a HuR-dependent manner. Hence, the fine-tuning of TNF-α mRNA stability by HuR and miR181 plays a crucial role in immunoparalysis, and Na(+),K(+)-ATPase ligands are promising agents for immunoparalysis therapy. BlackWell Publishing Ltd 2015-02 2014-12-22 /pmc/articles/PMC4328645/ /pubmed/25535255 http://dx.doi.org/10.15252/emmm.201404797 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Dan, Cao
Jinjun, Bian
Zi-Chun, Hua
Lin, Ma
Wei, Chen
Xu, Zhang
Ri, Zhou
Shun, Cheng
Wen-Zhu, Sun
Qing-Cai, Jiao
Wu, Yin
Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis
title Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis
title_full Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis
title_fullStr Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis
title_full_unstemmed Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis
title_short Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis
title_sort modulation of tnf-α mrna stability by human antigen r and mir181s in sepsis-induced immunoparalysis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328645/
https://www.ncbi.nlm.nih.gov/pubmed/25535255
http://dx.doi.org/10.15252/emmm.201404797
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