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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 | 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 |
| 3 | Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles 显示文摘 | Fickert P Zollner G Fuchsbichler A | 2002 | Gastroenterology2002，123，4： | 1 |
| 4 | 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 |
| 5 | Role of nuclear receptors andhepatocyte-enriched transcription factors for Ntcp repression inbiliary obstruction in mouse liver显示文摘 | Zollner G Wagner M Fickert P | 2005 | Am J Physiol GastrointestLiver Physiol2005，289，5： | 1 |
| 6 | Role of nuclear bile acid receptor FXR in adaptive ABC transporter regulation by cholic and ursodexycholic acid in mouse liver kidney and intestine 显示文摘 | Zollner G Fickert P Fuchsbichler A et a1 | 2003 | J Hepatol2003，39，4： | 1 |
| 7 | 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 |
| 8 | Bile acids as regulators of hepatic lipid and glucose metabolism显示文摘 | Trauner M Claudel T Fickert P Moustafa T Wagner M | 2010 | Dig Dis2010，28，1： | 1 |
| 9 | Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice显示文摘 | Fickert P Fuchsbichler A Wagner M | 2004 | Gastroenterology2004，127，1： | 1 |
| 10 | MDR3 (ABCB4) defects:a paradigm for the genetics of adult cholestatic syndromes显示文摘 | Tranner M Fickert P Wagner M | | 0，，01： | 1 |
| 11 | Mechanisms of disease : mecha- nisms and clinical implications of cholestasis in sepsis 显示文摘 | Geier A Fickert P Tranner M | 2006 | Nat Clin Pract Gastroenterol Hepatol2006，3，10： | 1 |
| 12 | Mechanisms of disease: mechan- isms and clinical implications of cholestasis in sepsis显示文摘 | Geier A Fickert P Trauner M | 2006 | Nat Clin Pract Gastroenterol Hepatol2006，3，10： | 1 |
| 13 | Hepatobiliary transporter expression in percutaneous liver biopsies of patients with choles- tatic liver diseases 显示文摘 | Zollner G Fickert P Zenz R | 2001 | Hepatology2001，33，3： | 1 |
| 14 | Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases显示文摘 | Zollner G Fickert P Zenz R | 2001 | Hepatology2001，33，3： | 1 |
| 15 | Molecuhr regula- tion of hepatobiliary transport systems cmcal inplica- tions for understanding and treating cholestasis显示文摘 | Trauner M Wagner M Fickert P | 2005 | Journal of Clinical Gastroenterology2005，17，2： | 1 |
| 16 | Pathogenesis of primary sclerosing cholangitis 显示文摘 | Pollheimer M J Halilbasic E Fickert P | 2011 | Best Pract Res Clin Gastroenterol2011，25，6： | 1 |
| 17 | A new xenobiotic-in- duced mouse model of sclerosing cholangitis and biliary fibrosis 显示文摘 | Fickert P Stoger U Fuchsbichler A | 2007 | Amj Pathol2007，171，2： | 1 |
| 18 | Increasedcarbohydrate-deficient transferrin during pregnancy:relation to sex hormones显示文摘 | Stauber RE Jauk B Fickert P | 1996 | Alcohol Alcohol1996，31，4： | 1 |
| 19 | Mechanisms of disease : mechanisms and clinical implications of cholestasis in sepsis显示文摘 | Geier A Fickert P Trauner M | 2006 | Nat Clin Pract Gastroenterol Hepato12006，3，10： | 1 |
| 20 | Chronic cholestatic liver diseases:Clues from histopathology for pathogenesis显示文摘 | Pollheimer MJ Fickert P Stieger B | 2013 | Mol Aspects Med2013，，： | 1 |
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