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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

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

EMBO Mol Med. 2015 Feb;7(2):140-57.

PMID: 25535255

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248889	TNF-α human			Price

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