All- trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production.

Background/Aims: Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all- trans-retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation- or bleomycin-induced lung fibrosis. Methods: We examined the impact of ATRA on carbon tetrachloride (CCl₄)-induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)-β1 and interleukin (IL)-6 in CCl₄-treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs. Results: CCl₄-induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA ( n=25), whereas it was 75.0% ( n=24) in the treatment group ( P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF-β1, IL-6 and collagen from HSCs, (ii) TGF-β-dependent transdifferentiation of the cells and IL-6-dependent cell proliferation and (iii) the activities of nuclear factor-κB p65 and p38mitogen-activated protein kinase, which stimulate the production of TGF-β1 and IL-6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis. Conclusions: Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]