title: 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 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.
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Cao
authors.initials: C
authors.lastname: Dan
authors.affiliation: Department of Anesthesiology and Intensive Care Unit, Changhai Hospital Affiliated Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Bian
authors.initials: B
authors.lastname: Jinjun
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zi-Chun
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Ma
authors.initials: M
authors.lastname: Lin
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology and Intensive Care Unit, Changhai Hospital Affiliated Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Ri
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Shun
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Sun
authors.initials: S
authors.lastname: Wen-Zhu
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Qing-Cai
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of life Sciences Nanjing University, Nanjing, China The State Key Lab of Natural Medicine, China Pharmaceutical University, Nanjing, China Jiangsu Key Lab of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine, Nanjing, China wyin@nju.edu.cn.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000818:Animals; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010042:Ouabain / Q000008:administration & dosage; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051959:ELAV Proteins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D010042:Ouabain
keywords: human antigen R; immunoparalysis; microRNA181; ouabain; tumor necrosis factor α