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Adenoviral Delivery of an Antisense RNA Complementary to the 3' Coding Sequence of Transforming Growth Factor-ß1 Inhibits Fibrogenic Activities of Hepatic Stellate Cells¹

Institute of Clinical Chemistry and Pathobiochemistry, RWTH- University Hospital, D-52074 Aachen, Germany

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)-ß1. This pluripotent, profibrogenic cytokine stimulates matrix synthesis and decreases matrix degradation, resulting in fibrosis. Thus, blockade of synthesis or sequestering of mature TGF-ß1 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-ß1 is able to suppress the synthesis of TGF-ß1 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-ß1 ELISA, and cell proliferation assays. Additionally, the biological function of the transgene was confirmed by analysis of differential activity of TGF-ß1-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-ß2, TGF-ß3, collagen type 1(I), latent transforming growth factor binding protein 1, types I and II TGF-ß receptors, and -smooth muscle actin. Our results indicate that the administration of antisense mRNA offers a feasible approach to block autocrine TGF-ß1 signaling in hepatic stellate cells and may be useful and applicable in future to the treatment of fibrosis in chronic liver diseases.

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