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

• Type of Material: Article
• Authors: Xian Fan, Emory University; Stephen T. Mills, Emory University; Mevelyn J. Kaalla, Mercer University; Viranuj Sueblinvong, Emory University
• Language: English
• Date: 2020-11-05
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-020-76148-5
• Title of Journal or Parent Work: Scientific Reports
• Volume: 10
• Grant/Funding Information: NIH K08 AA021404-01 (VS) and NIAAA R03 AA027335-01 (VS).
• Keywords: Cell biology; Molecular biology
• Research Categories: Biology, Molecular; Biology, Cell

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.