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Digestive Diseases and Sciences

, Volume 63, Issue 10, pp 2662–2672 | Cite as

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

  • Shouhua Zhang
  • Yuanqi Gong
  • Juhua Xiao
  • Yong Chai
  • Jun Lei
  • Hui Huang
  • Tianxin Xiang
  • Wei Shen
Original Article
  • 63 Downloads

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.

Keywords

Hepatic fibrosis TGF-β soluble receptor COL1A1 promoter Autoimmunity 

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant Numbers: 81760115 and 81460118), Education Department Scientific Research Foundation of Jiangxi Province (Grant Number: GJJ160039).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest exists.

Supplementary material

10620_2018_5168_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Shouhua Zhang
    • 1
    • 2
  • Yuanqi Gong
    • 1
    • 3
  • Juhua Xiao
    • 4
  • Yong Chai
    • 2
  • Jun Lei
    • 2
  • Hui Huang
    • 2
  • Tianxin Xiang
    • 5
  • Wei Shen
    • 3
  1. 1.Department of Comprehensive Intensive Care UnitThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
  2. 2.Department of General SurgeryJiangxi Provincial Children’s HospitalNanchangChina
  3. 3.Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
  4. 4.Department of UltrasoundJiangxi Provincial Maternal and Child Health HospitalNanchangChina
  5. 5.Department of Infectious DiseaseThe First Affiliated Hospital of Nanchang UniversityNanchangChina

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