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糖皮质激素诱导的微小RNA-511通过下调肿瘤坏死因子受体1（TNFR1）来抵御肿瘤坏死因子（TNF）。

Glucocorticoid-induced microRNA-511 protects against TNF by down-regulating TNFR1.

作者信息

Puimège Leen, Van Hauwermeiren Filip, Steeland Sophie, Van Ryckeghem Sara, Vandewalle Jolien, Lodens Sofie, Dejager Lien, Vandevyver Sofie, Staelens Jan, Timmermans Steven, Vandenbroucke Roosmarijn E, Libert Claude

机构信息

VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

出版信息

EMBO Mol Med. 2015 Aug;7(8):1004-17. doi: 10.15252/emmm.201405010.

DOI:10.15252/emmm.201405010
PMID:25995337
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4551340/
Abstract

TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effects of glucocorti-coids are mediated by induction of this miR, resulting in reduced TNFR1 expression.

摘要

肿瘤坏死因子（TNF）是炎症过程中的关键因子，也是炎症性疾病中公认的药物靶点。我们发现，以对TNF诱导的休克具有极端和显性抗性而闻名的小鼠品系SPRET/Ei，其肿瘤坏死因子受体1蛋白（TNFR1）表达较弱，但mRNA表达正常，这一特性在基因上与主要的TNFR1编码基因Tnfrsf1a以及一个包含预测的TNFR1调节性miR-511的基因座相关。这种微小RNA（miRNA）是细胞中真正的TNFR1调节因子。在小鼠中，miR-511的过表达下调TNFR1并对TNF具有保护作用，而抗miR-511则上调TNFR1并使小鼠对TNF敏感，从而打破了SPRET/Ei的抗性。我们发现miR-511可抑制内毒素血症和实验性肝炎，并且这种miR受到糖皮质激素的强烈诱导，是一种真正的TNFR1调节剂，因此是一种抗炎性miR。由于TNFR1的最小程度降低对TNF敏感性有相当大的影响，我们认为糖皮质激素的至少部分抗炎作用是通过诱导这种miR介导的，从而导致TNFR1表达降低。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/fb47714b8f34/emmm0007-1004-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/58537d971239/emmm0007-1004-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/3d4904cc6ac2/emmm0007-1004-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/c1e35abc7385/emmm0007-1004-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/73f394dfee08/emmm0007-1004-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/dedbfd0d102f/emmm0007-1004-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/fb47714b8f34/emmm0007-1004-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/58537d971239/emmm0007-1004-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/3d4904cc6ac2/emmm0007-1004-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/c1e35abc7385/emmm0007-1004-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/73f394dfee08/emmm0007-1004-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0be/4551340/dedbfd0d102f/emmm0007-1004-f5.jpg
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