Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis.
Modulation of TNF-α mRNA stability by human antigen R and miR181s in sepsis-induced immunoparalysis.
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DOI：
10.15252/emmm.201404797
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发表时间：
2015-02
影响因子：
11.1
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Dan C;Jinjun B;Zi-Chun H;Lin M;Wei C;Xu Z;Ri Z;Shun C;Wen-Zhu S;Qing-Cai J;Wu Y
免疫麻痹是脓毒症的重要病理机制。然而，缺乏有效的小分子治疗。在这里，我们表明哇巴因，Na+，K+-ATP酶的配体，可以逆转免疫麻痹在体外，体内，和临床样本。值得注意的是，哇巴因的作用严重依赖于TNF-α的表达。然而，哇巴因对TNF-α mRNA的稳定性有相反的作用：哇巴因触发miR-181转录，促进TNF-α mRNA降解，诱导免疫瘫痪;哇巴因触发人类抗原R（HuR）核输出，稳定TNF-α mRNA，抑制免疫瘫痪。有趣的是，由于miR-181结合位点位于TNF-α 3′-非翻译区的HuR结合位点内，在哇巴因处理的细胞中，HuR与miR-181竞争结合TNF-α mRNA，并将TNF-α mRNA募集到应激颗粒中，从而稳定TNF-α mRNA并逆转免疫麻痹。哇巴因还以HuR依赖性方式诱导GM-CSF和干扰素-γ表达。因此，HuR和miR 181对TNF-α mRNA稳定性的微调在免疫麻痹中起着至关重要的作用，Na+，K+-ATP酶配体是用于免疫麻痹治疗的有希望的药剂。
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.