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

被引：57

作者：

Cao Dan ^{[1
]}

Bian Jinjun ^{[2
]}

Hua Zi‐Chun ^{[1
]}

Ma Lin ^{[1
]}

Chen Wei ^{[1
]}

Zhang Xu ^{[2
]}

Zhou Ri ^{[1
]}

Cheng Shun ^{[1
]}

Sun Wen‐Zhu ^{[1
]}

Jiao Qing‐Cai ^{[1
]}

Yin Wu ^{[1
]}

机构：

[1] College of life Sciences,The State Key Lab of Pharmaceutical Biotechnology

[2] Nanjing University,Department of Anesthesiology and Intensive Care Unit

[3] Changhai Hospital,The State Key Lab of Natural Medicine

[4] Affiliated Hospital of the Second Military Medical University,Jiangsu Key Lab of Pediatric Respiratory Disease

[5] China Pharmaceutical University,undefined

[6] Nanjing University of Chinese Medicine,undefined

来源：

EMBO Molecular Medicine | 2015年 / 7卷 / 2期

关键词：

human antigen R; immunoparalysis; microRNA181; ouabain; tumor necrosis factor α;

D O I：

10.15252/emmm.201404797

中图分类号：

学科分类号：

摘要：

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.

引用

页码：140 / 157

页数：17

共 266 条

[1] Bagrov AY(2009)Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets Pharmacol Rev 61 9-38
[2] Shapiro JI(2003)Endogenous glycosides in critically ill patients Crit Care Med 31 1331-1337
[3] Fedorova OV(2009)Endotoxin tolerance: new mechanisms, molecules and clinical significance Trends Immunol 30 475-487
[4] Berendes E(2003)Sublethal hemorrhage induces tolerance in animals exposed to cecal ligation and puncture by altering p38, p44/42, and SAPK/JNK MAP kinase activation Surg Infect 4 17-27
[5] Cullen P(2000)Intrapulmonary TNF gene therapy reverses sepsis‐induced suppression of lung antibacterial host defense J Immunol 165 6496-6503
[6] Van Aken H(2005)Real‐time quantification of microRNAs by stem–loop RT–PCR Nucleic Acids Res 33 e179-681
[7] Zidek W(1997)Monocyte deactivation in septic patients: restoration by IFN‐gamma treatment Nat Med 3 678-5380
[8] Erren M(2007)The RNA‐binding protein HuR promotes cell migration and cell invasion by stabilizing the beta‐actin mRNA in a U‐rich‐element‐dependent manner Mol Cell Biol 27 5365-389
[9] Hubschen M(2003)Treatment of experimental sepsis‐induced immunoparalysis with TNF Immunobiology 208 381-124
[10] Weber T(2006)Changes in ion transport in inflammatory disease J Inflamm 3 5-784

← 1 2 3 4 5 6 7 8 9 10 →