A COL1A1 Promoter-Controlled Expression of TGF-β Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses
Soluble TGF-β1 type II receptor (sTβRII) via TGF-β1 inhibition could inhibit hepatic fibrosis, but over-dosage triggers autoimmune responses.
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.
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.
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.
COL1A1 can precisely control sTβRII expression to inhibit excessive bioactive TGF-β level and thus inhibit hepatic fibrosis but without inducing autoimmune responses.
KeywordsHepatic fibrosis TGF-β soluble receptor COL1A1 promoter Autoimmunity
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).
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Conflict of interest
The authors declare that there is no conflict of interest exists.
- 14.Shea P, Hirschfield G, Shiffman M, et al. PS-002-Common variation near glial-derived neurotrophic factor is associated with progression of hepatic collagen content in a genome-wide association study of liver fibrosis phenotypes in patients with primary sclerosing cholangitis. J Hepatol. 2017;66:S4–S5.CrossRefGoogle Scholar
- 23.Marquez-Aguirre A, Sandoval-Rodriguez A, Gonzalez-Cuevas J, et al. Adenoviral delivery of dominant-negative transforming growth factor β type II receptor up-regulates transcriptional repressor SKI-like oncogene, decreases matrix metalloproteinase 2 in hepatic stellate cell and prevents liver fibrosis in rats. J Gene Med. 2009;11:207–219.CrossRefPubMedGoogle Scholar