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酒精通过下调小鼠肺成纤维细胞中的miR-1946a来诱导转化生长因子β1（TGFβ1）。

Alcohol induces TGFβ1 via downregulation of miR-1946a in murine lung fibroblast.

作者信息

Fan Xian, Mills Stephen T, Kaalla Mevelyn J, Sueblinvong Viranuj

机构信息

Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University School of Medicine, 615 Michael Street, Suite 205, Atlanta, GA, 30322, USA.

Mercer University Health Sciences Center, Macon, GA, 31207, USA.

出版信息

Sci Rep. 2020 Nov 5;10(1):19089. doi: 10.1038/s41598-020-76148-5.

DOI:10.1038/s41598-020-76148-5
PMID:33154445
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7644620/
Abstract

Exaggerated transforming growth factor-beta 1 (TGFβ1) expression worsens fibroproliferation following bleomycin-induced lung injury in alcohol-fed mice. MicroRNA (miR)-1946a is predicted to bind to the TGFβ1 3' untranslated region (UTR), thereby inhibiting its transcription. We hypothesize that alcohol suppresses miR-1946a and induces TGFβ1. Primary murine lung fibroblasts (PLFs) were cultured ± alcohol, miR-1946a mimic or inhibitor, and TGFβ1 signaling inhibitors. miR-1946a was analyzed after alcohol treatment in vitro and in vivo. TGFβ1 expression and TGFβ1 3'UTR-luciferase activity was quantified. We showed that alcohol suppressed miR-1946a in the alcohol-fed mouse lungs and PLFs. MiR-1946a inhibitor increased TGFβ1 expression in the fibroblast. MiR-1946a mimic treatment suppressed TGFβ1 gene expression and TGFβ1 3'UTR activity. Overexpression of miR1946a inhibited alcohol-induced TGFβ1 gene and protein expression as well as alcohol-induced TGFβ1 and α-smooth muscle actin (SMA) protein expression in PLFs. In conclusion, miR-1946a modulates TGFβ1 expression through direct interaction with TGFβ1 3'UTR. These findings identify a novel mechanism by which alcohol induces TGFβ1 in the lung.

摘要

在酒精喂养的小鼠中，转化生长因子-β1（TGFβ1）表达的过度增强会使博来霉素诱导的肺损伤后的纤维增生恶化。预测微小RNA（miR）-1946a可与TGFβ1的3'非翻译区（UTR）结合，从而抑制其转录。我们推测酒精会抑制miR-1946a并诱导TGFβ1。将原代小鼠肺成纤维细胞（PLF）在有或无酒精、miR-1946a模拟物或抑制剂以及TGFβ1信号抑制剂的条件下培养。在体外和体内酒精处理后分析miR-1946a。对TGFβ1表达和TGFβ1 3'UTR荧光素酶活性进行定量。我们发现酒精会抑制酒精喂养的小鼠肺组织和PLF中的miR-1946a。miR-1946a抑制剂可增加成纤维细胞中TGFβ1的表达。miR-1946a模拟物处理可抑制TGFβ1基因表达和TGFβ1 3'UTR活性。miR1946a的过表达抑制了酒精诱导的PLF中TGFβ1基因和蛋白表达以及酒精诱导的TGFβ1和α-平滑肌肌动蛋白（SMA）蛋白表达。总之，miR-1946a通过与TGFβ1 3'UTR直接相互作用来调节TGFβ1表达。这些发现确定了酒精在肺中诱导TGFβ1的一种新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/3278740188ee/41598_2020_76148_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/78d99353848f/41598_2020_76148_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/b4c6c4f5a63a/41598_2020_76148_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/d2a830fb5a6d/41598_2020_76148_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/a63579452b16/41598_2020_76148_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/f9735f38dc55/41598_2020_76148_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/6f760ce965ed/41598_2020_76148_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/5b40d1633b3c/41598_2020_76148_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/3278740188ee/41598_2020_76148_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/78d99353848f/41598_2020_76148_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/b4c6c4f5a63a/41598_2020_76148_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/d2a830fb5a6d/41598_2020_76148_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/a63579452b16/41598_2020_76148_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/f9735f38dc55/41598_2020_76148_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/6f760ce965ed/41598_2020_76148_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/5b40d1633b3c/41598_2020_76148_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c779/7644620/3278740188ee/41598_2020_76148_Fig8_HTML.jpg

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