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| 1 | Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model显示文摘AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice. | Florian P Reiter Ralf Wimmer Lena Wottke Renate Artmann Jutta M Nagel Manuel O Carranza Doris Mayr Christian Rust Peter Fickert Michael Trauner Alexander L Gerbes Simon Hohenester Gerald U Denk | 2016 | World Journal of Hepatology2016，8，8： | 3 |
| 2 | How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma显示文摘 | Florian Hucke Matthias Pinter Ivo Graziadei Simona Bota Wolfgang Vogel Christian Müller Harald Heinzl Fredrik Waneck Michael Trauner Markus Peck-Radosavljevic Wolfgang Sieghart | 2014 | Journal of Hepatology2014，，： | 2 |
| 3 | New paradigms in the treatment of hepatic cholestasis:from UDCA to FXR,PXR and beyond显示文摘 | Beuers U Trauner M Jansen P | 2015 | J Hepatol2015，，： | 1 |
| 4 | Nuclear receptors as therapeutic targets in cholestatic liver diseases显示文摘 | Zollner G Trauner M | 2009 | Br J Pharmacol2009，156，1： | 1 |
| 5 | Expression of the bile salt export pump is maintained after chronic cholestasis in the rat 显示文摘 | Lee JM Trauner M Soroka CJ | 2000 | Gastroenterology2000，118，1： | 1 |
| 6 | MDR3(ABCB4)defects:a paradigm for the gentics of adult cholestatic syndromes显示文摘 | Trauner M Ficker P Wsgner M | | 0，，： | 1 |
| 7 | New paradigms in the treatment of hepatic cholestasis:from UDCA to FXR,PXR and beyond显示文摘 | Beuers U Trauner M Jansen P et a1 | 2015 | J Hepatol2015，，： | 1 |
| 8 | Molecular regulation of hepatocellular transport system in cholestasis显示文摘 | Meier DG Boyer JL | 1999 | Hepatology1999，31，： | 1 |
| 9 | Molecular pathogenesis ofcholestasis显示文摘 | Trauner M Meierer P J Boyer JL | 1998 | New Eng J Med1998，339，17： | 1 |
| 10 | Molecular regulation of hepatocellular transport systems in cholestasis 显示文摘 | Trauner M Meier DJ Boyer JL | 1999 | Hepatology1999，31，1： | 1 |
| 11 | Bile salt transporters:molecularcharacterization,function,and regulation显示文摘 | Trauner M Boyer JL | 2003 | Physiol Rev2003，83，2： | 1 |
| 12 | Molecular pathogenesis of cholestasis显示文摘 | Zollner G Trauner M | 2006 | Wien Med Wochenschr2006，156，1314： | 1 |
| 13 | Bile acid transporters and regulatory nuclear receptors in the liver and beyond显示文摘 | Halilbasic E Claudel T Trauner M | 2013 | J Hepatol2013，58，1： | 1 |
| 14 | Molecular regulation of hepatobiliary transport systems:clinical implications for understanding and treating cholestasis显示文摘 | Trauner M Wagner M Fickert P | 2005 | J Clin Gastroenterol2005，39，412： | 1 |
| 15 | Oncosis represents the main type of cell death in mouse models of cholestasis显示文摘 | Fickert P Trauner M Fuchsbichler A | 2005 | J Hepatol2005，42，3： | 1 |
| 16 | Maternal cholestasis does not affect the ontogenic pattern of expression of the Na^+/taurocholate cotransporting polypeptide (ntcp) in the fetal and neonatal rat and neonatal rat liver显示文摘 | Arrese M Trauner M Boyer J L | 1998 | Hepatology1998，28，3： | 1 |
| 17 | Cholestatic syndromes 显示文摘 | Trauner M Boyer JL | 2002 | Curr Opin Gastroenterol2002，18，3： | 1 |
| 18 | New molecular insights into the mechanisms of cholestasis显示文摘 | Wagner M Zollner G Trauner M | 2009 | J Hepatol2009，51，3： | 1 |
| 19 | Oncosis represents the main type of cell death in mouse models of cholestasis 显示文摘 | Fickert P Trauner M Fuchsbichler A | 2005 | J Hepatol2005，42，3： | 1 |
| 20 | Mechanisms of cholestasis显示文摘 | Zollner G Trauner M | 2008 | Clin Liver Dis2008，12，1： | 1 |
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