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Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 10/2018

01-10-2018 | Original Article

A COL1A1 Promoter-Controlled Expression of TGF-β Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses

Authors: Shouhua Zhang, Yuanqi Gong, Juhua Xiao, Yong Chai, Jun Lei, Hui Huang, Tianxin Xiang, Wei Shen

Published in: Digestive Diseases and Sciences | Issue 10/2018

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Abstract

Background

Soluble TGF-β1 type II receptor (sTβRII) via TGF-β1 inhibition could inhibit hepatic fibrosis, but over-dosage triggers autoimmune responses.

Aim

To test whether the use of a TGF-β1-responsive collagen I promoter COL1A1, via generating a feedback loop to TGF-β1 level, could offer accurate control on sTβRII expression.

Methods

Recombinant adenoviruses with COL1A1 (Ad-COL-sTβRII/Luc) or CMV promoter (Ad-CMV-sTβRII/Luc) were constructed and characterized. Inhibition of TGF-β activity was determined both in vitro and in vivo. Total and bioactive TGF-β, hepatic fibrosis scale, α-SMA, collagen levels, and liver function were determined.

Results

COL1A1, but not CMV, responded to TGF-β1 in vitro. Both in vitro and in vivo, Ad-COL-sTβRII could significantly, but not completely inhibit TGF-β1 activity while Ad-CMV-sTβRII almost completely inhibited TGF-β1 activity. As evidenced by fibrosis scale, α-SMA, and collagen levels in liver tissue, Ad-COL-sTβRII and Ad-CMV-sTβRII had comparable efficacies in treating hepatic fibrosis. Ad-COL-sTβRII was better than Ad-CMV-sTβRII in liver function restore. Ad-CMV-sTβRII, but not Ad-COL-sTβRII, induced high level of anti-dsDNA and anti-Sm antibodies in rats.

Conclusions

COL1A1 can precisely control sTβRII expression to inhibit excessive bioactive TGF-β level and thus inhibit hepatic fibrosis but without inducing autoimmune responses.
Appendix
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Metadata
Title
A COL1A1 Promoter-Controlled Expression of TGF-β Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses
Authors
Shouhua Zhang
Yuanqi Gong
Juhua Xiao
Yong Chai
Jun Lei
Hui Huang
Tianxin Xiang
Wei Shen
Publication date
01-10-2018
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 10/2018
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-018-5168-3

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