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Adenoviral delivery of an antisense RNA complementary to the 3' coding sequence of transforming growth factor-beta1 inhibits fibrogenic activities of hepatic stellate cells.
Cell Growth Differ. 2002 Jun; 13(6):265-73.CG

Abstract

Liver fibrosis occurs as a consequence of the transdifferentiationof hepatic stellate cells into myofibroblasts and is associated with an increased expression and activation of transforming growth factor (TGF)-beta1. This pluripotent, profibrogenic cytokine stimulates matrix synthesis and decreases matrix degradation, resulting in fibrosis. Thus, blockade of synthesis or sequestering of mature TGF-beta1 is a primary target for the development of antifibrotic approaches. The purpose of this study was to investigate whether the administration of adenoviruses constitutively expressing an antisense mRNA complementary to the 3' coding sequence of TGF-beta1 is able to suppress the synthesis of TGF-beta1 in culture-activated hepatic stellate cells. We demonstrate that the adenoviral vehicle directs high-level expression of the transgene and proved that the transduced antisense is biologically active by immunoprecipitation, Western blot, quantitative TGF-beta1 ELISA, and cell proliferation assays. Additionally, the biological function of the transgene was confirmed by analysis of differential activity of TGF-beta1-responsive genes using cell ELISA, Northern blotting, and by microarray technology, respectively. Furthermore, we examined the effects of that transgene on the expression of TGF-beta2, TGF-beta3, collagen type alpha1(I), latent transforming growth factor binding protein 1, types I and II TGF-beta receptors, and alpha-smooth muscle actin. Our results indicate that the administration of antisense mRNA offers a feasible approach to block autocrine TGF-beta1 signaling in hepatic stellate cells and may be useful and applicable in future to the treatment of fibrosis in chronic liver diseases.

Authors+Show Affiliations

Institute of Clinical Chemistry and Pathobiochemistry, RWTH- University Hospital, D-52074 Aachen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12114216

Citation

Arias, Monica, et al. "Adenoviral Delivery of an Antisense RNA Complementary to the 3' Coding Sequence of Transforming Growth Factor-beta1 Inhibits Fibrogenic Activities of Hepatic Stellate Cells." Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research, vol. 13, no. 6, 2002, pp. 265-73.
Arias M, Lahme B, Van de Leur E, et al. Adenoviral delivery of an antisense RNA complementary to the 3' coding sequence of transforming growth factor-beta1 inhibits fibrogenic activities of hepatic stellate cells. Cell Growth Differ. 2002;13(6):265-73.
Arias, M., Lahme, B., Van de Leur, E., Gressner, A. M., & Weiskirchen, R. (2002). Adenoviral delivery of an antisense RNA complementary to the 3' coding sequence of transforming growth factor-beta1 inhibits fibrogenic activities of hepatic stellate cells. Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research, 13(6), 265-73.
Arias M, et al. Adenoviral Delivery of an Antisense RNA Complementary to the 3' Coding Sequence of Transforming Growth Factor-beta1 Inhibits Fibrogenic Activities of Hepatic Stellate Cells. Cell Growth Differ. 2002;13(6):265-73. PubMed PMID: 12114216.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adenoviral delivery of an antisense RNA complementary to the 3' coding sequence of transforming growth factor-beta1 inhibits fibrogenic activities of hepatic stellate cells. AU - Arias,Monica, AU - Lahme,Birgit, AU - Van de Leur,Eddy, AU - Gressner,Axel M, AU - Weiskirchen,Ralf, PY - 2002/7/13/pubmed PY - 2003/1/11/medline PY - 2002/7/13/entrez SP - 265 EP - 73 JF - Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research JO - Cell Growth Differ VL - 13 IS - 6 N2 - Liver fibrosis occurs as a consequence of the transdifferentiationof hepatic stellate cells into myofibroblasts and is associated with an increased expression and activation of transforming growth factor (TGF)-beta1. This pluripotent, profibrogenic cytokine stimulates matrix synthesis and decreases matrix degradation, resulting in fibrosis. Thus, blockade of synthesis or sequestering of mature TGF-beta1 is a primary target for the development of antifibrotic approaches. The purpose of this study was to investigate whether the administration of adenoviruses constitutively expressing an antisense mRNA complementary to the 3' coding sequence of TGF-beta1 is able to suppress the synthesis of TGF-beta1 in culture-activated hepatic stellate cells. We demonstrate that the adenoviral vehicle directs high-level expression of the transgene and proved that the transduced antisense is biologically active by immunoprecipitation, Western blot, quantitative TGF-beta1 ELISA, and cell proliferation assays. Additionally, the biological function of the transgene was confirmed by analysis of differential activity of TGF-beta1-responsive genes using cell ELISA, Northern blotting, and by microarray technology, respectively. Furthermore, we examined the effects of that transgene on the expression of TGF-beta2, TGF-beta3, collagen type alpha1(I), latent transforming growth factor binding protein 1, types I and II TGF-beta receptors, and alpha-smooth muscle actin. Our results indicate that the administration of antisense mRNA offers a feasible approach to block autocrine TGF-beta1 signaling in hepatic stellate cells and may be useful and applicable in future to the treatment of fibrosis in chronic liver diseases. SN - 1044-9523 UR - https://www.unboundmedicine.com/medline/citation/12114216/Adenoviral_delivery_of_an_antisense_RNA_complementary_to_the_3'_coding_sequence_of_transforming_growth_factor_beta1_inhibits_fibrogenic_activities_of_hepatic_stellate_cells_ L2 - http://cgd.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12114216 DB - PRIME DP - Unbound Medicine ER -