Modulation of TNF‐α mRNA stability by human antigen R and miR181s in sepsis‐induced immunoparalysis
Abstract 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 criticall...
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Springer Nature
2014-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404797 |
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| author | Cao Dan Bian Jinjun Hua Zi‐Chun Ma Lin Chen Wei Zhang Xu Zhou Ri Cheng Shun Sun Wen‐Zhu Jiao Qing‐Cai Yin Wu |
| author_facet | Cao Dan Bian Jinjun Hua Zi‐Chun Ma Lin Chen Wei Zhang Xu Zhou Ri Cheng Shun Sun Wen‐Zhu Jiao Qing‐Cai Yin Wu |
| author_sort | Cao Dan |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-cbc0c8aff9524431ae27ac1e86b40f97 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2014-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-cbc0c8aff9524431ae27ac1e86b40f972025-08-20T03:06:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842014-12-017214015710.15252/emmm.201404797Modulation of TNF‐α mRNA stability by human antigen R and miR181s in sepsis‐induced immunoparalysisCao Dan0Bian Jinjun1Hua Zi‐Chun2Ma Lin3Chen Wei4Zhang Xu5Zhou Ri6Cheng Shun7Sun Wen‐Zhu8Jiao Qing‐Cai9Yin Wu10The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityDepartment of Anesthesiology and Intensive Care Unit, Changhai Hospital, Affiliated Hospital of the Second Military Medical UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityDepartment of Anesthesiology and Intensive Care Unit, Changhai Hospital, Affiliated Hospital of the Second Military Medical UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityThe State Key Lab of Pharmaceutical Biotechnology, College of life Sciences, Nanjing UniversityAbstract 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.https://doi.org/10.15252/emmm.201404797human antigen RimmunoparalysismicroRNA181ouabaintumor necrosis factor α |
| spellingShingle | Cao Dan Bian Jinjun Hua Zi‐Chun Ma Lin Chen Wei Zhang Xu Zhou Ri Cheng Shun Sun Wen‐Zhu Jiao Qing‐Cai Yin Wu Modulation of TNF‐α mRNA stability by human antigen R and miR181s in sepsis‐induced immunoparalysis EMBO Molecular Medicine human antigen R immunoparalysis microRNA181 ouabain tumor necrosis factor α |
| 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 | human antigen R immunoparalysis microRNA181 ouabain tumor necrosis factor α |
| url | https://doi.org/10.15252/emmm.201404797 |
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