Skip to main content
Erschienen in: Digestive Diseases and Sciences 10/2018

23.06.2018 | Original Article

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

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

Erschienen in: Digestive Diseases and Sciences | Ausgabe 10/2018

Einloggen, um Zugang zu erhalten

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.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002;7:d793–d807.CrossRefPubMed Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002;7:d793–d807.CrossRefPubMed
2.
Zurück zum Zitat Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247–2250.CrossRefPubMed Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247–2250.CrossRefPubMed
3.
Zurück zum Zitat Castilla A, Prieto J, Fausto N. Transforming growth factors β1 and α in chronic liver disease Effects of interferon alfa therapy. N Eng J Med. 1991;324:933–940.CrossRef Castilla A, Prieto J, Fausto N. Transforming growth factors β1 and α in chronic liver disease Effects of interferon alfa therapy. N Eng J Med. 1991;324:933–940.CrossRef
4.
Zurück zum Zitat Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA. The role of TGFβ1 in initiating hepatic stellate cell activation in vivo. J Hepatol. 1999;30:77–87.CrossRefPubMed Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA. The role of TGFβ1 in initiating hepatic stellate cell activation in vivo. J Hepatol. 1999;30:77–87.CrossRefPubMed
5.
Zurück zum Zitat Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010;7:425–436.CrossRefPubMed Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010;7:425–436.CrossRefPubMed
6.
Zurück zum Zitat Li Y, Wang W, Jia X, et al. A targeted multiple antigenic peptide vaccine augments the immune response to self TGF-β1 and suppresses ongoing hepatic fibrosis. Arch Immunol Ther Exp. 2015;63:305–315.CrossRef Li Y, Wang W, Jia X, et al. A targeted multiple antigenic peptide vaccine augments the immune response to self TGF-β1 and suppresses ongoing hepatic fibrosis. Arch Immunol Ther Exp. 2015;63:305–315.CrossRef
7.
Zurück zum Zitat Yata Y, Gotwals P, Koteliansky V, Rockey DC. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-β soluble receptor: implications for antifibrotic therapy. Hepatology. 2002;35:1022–1030.CrossRefPubMed Yata Y, Gotwals P, Koteliansky V, Rockey DC. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-β soluble receptor: implications for antifibrotic therapy. Hepatology. 2002;35:1022–1030.CrossRefPubMed
8.
Zurück zum Zitat Wu L, Zhang Q, Mo W, et al. Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-β1/Smads and PI3K/Akt pathways. Sci Rep. 2017;7:9289.CrossRefPubMedPubMedCentral Wu L, Zhang Q, Mo W, et al. Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-β1/Smads and PI3K/Akt pathways. Sci Rep. 2017;7:9289.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat George J, Roulot D, Koteliansky VE, Bissell DM. In vivo inhibition of rat stellate cell activation by soluble transforming growth factor β type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci USA. 1999;96:12719–12724.CrossRefPubMed George J, Roulot D, Koteliansky VE, Bissell DM. In vivo inhibition of rat stellate cell activation by soluble transforming growth factor β type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci USA. 1999;96:12719–12724.CrossRefPubMed
10.
Zurück zum Zitat Meng X-m, Nikolic-Paterson DJ, Lan HY. TGF-[beta]: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–338.CrossRefPubMed Meng X-m, Nikolic-Paterson DJ, Lan HY. TGF-[beta]: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–338.CrossRefPubMed
11.
Zurück zum Zitat Böttinger EP, Bitzer M. TGF-β signaling in renal disease. J Am Soc Nephrol. 2002;13:2600–2610.CrossRefPubMed Böttinger EP, Bitzer M. TGF-β signaling in renal disease. J Am Soc Nephrol. 2002;13:2600–2610.CrossRefPubMed
12.
Zurück zum Zitat Meng X-M, Chung AC, Lan HY. Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clin Sci. 2013;124:243–254.CrossRefPubMed Meng X-M, Chung AC, Lan HY. Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clin Sci. 2013;124:243–254.CrossRefPubMed
14.
Zurück zum Zitat 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.CrossRef 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.CrossRef
15.
Zurück zum Zitat Stefanovic B, Hellerbrand C, Brenner D. Regulatory role of the conserved stem-loop structure at the 5′ end of collagen α1 (I) mRNA. Mol Cell Biol. 1999;19:4334–4342.CrossRefPubMedPubMedCentral Stefanovic B, Hellerbrand C, Brenner D. Regulatory role of the conserved stem-loop structure at the 5′ end of collagen α1 (I) mRNA. Mol Cell Biol. 1999;19:4334–4342.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Kalajzic I, Kalajzic Z, Kaliterna M, et al. Use of type I collagen green fluorescent protein transgenes to identify subpopulations of cells at different stages of the osteoblast lineage. J Bone Miner Res. 2002;17:15–25.CrossRefPubMed Kalajzic I, Kalajzic Z, Kaliterna M, et al. Use of type I collagen green fluorescent protein transgenes to identify subpopulations of cells at different stages of the osteoblast lineage. J Bone Miner Res. 2002;17:15–25.CrossRefPubMed
17.
Zurück zum Zitat Chen P, Li J, Huo Y, et al. Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats. Sci Rep. 2016;6:33593.CrossRefPubMedPubMedCentral Chen P, Li J, Huo Y, et al. Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats. Sci Rep. 2016;6:33593.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Khan SA, Joyce J, Tsuda T. Quantification of active and total transforming growth factor-β levels in serum and solid organ tissues by bioassay. BMC Res Notes. 2012;5:636.CrossRefPubMedPubMedCentral Khan SA, Joyce J, Tsuda T. Quantification of active and total transforming growth factor-β levels in serum and solid organ tissues by bioassay. BMC Res Notes. 2012;5:636.CrossRefPubMedPubMedCentral
19.
20.
Zurück zum Zitat Hu K, Luo S, Tong L, et al. CCL19 and CCL28 augment mucosal and systemic immune responses to HIV-1 gp140 by mobilizing responsive immunocytes into secondary lymph nodes and mucosal tissue. J Immunol. 2013;191:1935–1947.CrossRefPubMed Hu K, Luo S, Tong L, et al. CCL19 and CCL28 augment mucosal and systemic immune responses to HIV-1 gp140 by mobilizing responsive immunocytes into secondary lymph nodes and mucosal tissue. J Immunol. 2013;191:1935–1947.CrossRefPubMed
21.
Zurück zum Zitat Kolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med. 2001;163:770–777.CrossRefPubMed Kolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med. 2001;163:770–777.CrossRefPubMed
22.
Zurück zum Zitat Kaji K, Yoshiji H, Ikenaka Y, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol. 2014;49:481–491.CrossRefPubMed Kaji K, Yoshiji H, Ikenaka Y, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol. 2014;49:481–491.CrossRefPubMed
23.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
24.
Zurück zum Zitat Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol. 2002;36:200–209.CrossRefPubMed Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol. 2002;36:200–209.CrossRefPubMed
25.
Zurück zum Zitat Aoki CA, Borchers AT, Li M, et al. Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmun Rev. 2005;4:450–459.CrossRefPubMed Aoki CA, Borchers AT, Li M, et al. Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmun Rev. 2005;4:450–459.CrossRefPubMed
26.
Zurück zum Zitat Meng XM, Zhang Y, Huang XR, Ren GL, Li J, Lan HY. Treatment of renal fibrosis by rebalancing TGF-beta/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015;6:36984–36997.PubMedPubMedCentral Meng XM, Zhang Y, Huang XR, Ren GL, Li J, Lan HY. Treatment of renal fibrosis by rebalancing TGF-beta/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015;6:36984–36997.PubMedPubMedCentral
27.
Zurück zum Zitat Kumar V, Mondal G, Dutta R, Mahato RI. Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis. Biomaterials. 2016;76:144–156.CrossRefPubMed Kumar V, Mondal G, Dutta R, Mahato RI. Co-delivery of small molecule hedgehog inhibitor and miRNA for treating liver fibrosis. Biomaterials. 2016;76:144–156.CrossRefPubMed
28.
Zurück zum Zitat Smekalova EM, Kotelevtsev YV, Leboeuf D, et al. lncRNA in the liver: prospects for fundamental research and therapy by RNA interference. Biochimie. 2016;131:159–172.CrossRefPubMed Smekalova EM, Kotelevtsev YV, Leboeuf D, et al. lncRNA in the liver: prospects for fundamental research and therapy by RNA interference. Biochimie. 2016;131:159–172.CrossRefPubMed
29.
Zurück zum Zitat Van Beneden K, Mannaerts I, Pauwels M, Van den Branden C, Van Grunsven LA. HDAC inhibitors in experimental liver and kidney fibrosis. Fibrogenesis Tissue Repair. 2013;6:1.CrossRefPubMedPubMedCentral Van Beneden K, Mannaerts I, Pauwels M, Van den Branden C, Van Grunsven LA. HDAC inhibitors in experimental liver and kidney fibrosis. Fibrogenesis Tissue Repair. 2013;6:1.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Kolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med. 2001;163:770–777.CrossRefPubMed Kolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med. 2001;163:770–777.CrossRefPubMed
31.
Zurück zum Zitat Aoki CA, Borchers AT, Li M, et al. Transforming growth factor β (TGF-β) and autoimmunity. Autoimmun Rev. 2005;4:450–459.CrossRefPubMed Aoki CA, Borchers AT, Li M, et al. Transforming growth factor β (TGF-β) and autoimmunity. Autoimmun Rev. 2005;4:450–459.CrossRefPubMed
32.
Zurück zum Zitat Rossi P, Karsenty G, Roberts AB, Roche NS, Sporn MB, de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-β. Cell. 1988;52:405–414.CrossRefPubMed Rossi P, Karsenty G, Roberts AB, Roche NS, Sporn MB, de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-β. Cell. 1988;52:405–414.CrossRefPubMed
33.
Zurück zum Zitat Ritzenthaler JD, Goldstein RH, Fine A, Smith BD. Regulation of the alpha 1 (I) collagen promoter via a transforming growth factor-beta activation element. J Biol Chem. 1993;268:13625–13631.PubMed Ritzenthaler JD, Goldstein RH, Fine A, Smith BD. Regulation of the alpha 1 (I) collagen promoter via a transforming growth factor-beta activation element. J Biol Chem. 1993;268:13625–13631.PubMed
34.
Zurück zum Zitat Hinz B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 2015;47:54–65.CrossRefPubMed Hinz B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 2015;47:54–65.CrossRefPubMed
35.
Zurück zum Zitat Kinoshita K, Iimuro Y, Otogawa K, et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut. 2007;56:706–714.CrossRefPubMed Kinoshita K, Iimuro Y, Otogawa K, et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut. 2007;56:706–714.CrossRefPubMed
36.
Zurück zum Zitat Ibraheem D, Elaissari A, Fessi H. Gene therapy and DNA delivery systems. Int J Pharm. 2014;459:70–83.CrossRefPubMed Ibraheem D, Elaissari A, Fessi H. Gene therapy and DNA delivery systems. Int J Pharm. 2014;459:70–83.CrossRefPubMed
Metadaten
Titel
A COL1A1 Promoter-Controlled Expression of TGF-β Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses
verfasst von
Shouhua Zhang
Yuanqi Gong
Juhua Xiao
Yong Chai
Jun Lei
Hui Huang
Tianxin Xiang
Wei Shen
Publikationsdatum
23.06.2018
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 10/2018
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-018-5168-3

Weitere Artikel der Ausgabe 10/2018

Digestive Diseases and Sciences 10/2018 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.