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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 | Variable Zinc coordination in endostatin显示文摘 | Hohenester E Sasaki T Mann K | 2000 | J Mol Biol2000，297，1： | 1 |
| 3 | Structural insight into Slit-Robo signaling显示文摘 | Hohenester E | 2008 | Biochem Soc Trans2008，36，2： | 1 |
| 4 | Collagen recognition and transmembrane signalling by discoidin domain receptors 显示文摘 | Carafoli F Hohenester E | 2013 | Biochim Biophys Acta2013，1834，10： | 1 |
| 5 | Collagen recognition and transmembrane signalling by discoidin domain receptors 显示文摘 | CARAFOLI F HOHENESTER E | 2013 | Biochim Biophys Acta2013，1834，10： | 1 |
| 6 | The biliary HCO3' umbrella-A unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies显示文摘 | Beuers U Hohenester S Maillette de Buy Wenniger LJ | 2010 | Hepatology2010，52，4： | 1 |
| 7 | Variable zinc coordination in endostatin显示文摘 | Hohenester E Sasaki T Mann K | 2000 | J Mol Biol2000，297，1： | 1 |
| 8 | A biliary HCO3' umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes显示文摘 | Hohenester S Wenniger LM Paulusma CC | 2012 | Hepatology2012，55，1： | 1 |
| 9 | Variable zinc coordination in endostatin显示文摘 | Hohenester E Sasaki T Mann K | | 0，，： | 1 |
| 10 | Novel fold revealed by the structure of a FAS1 domain pair from the insect cell adhesion molecule fasciclin Ⅰ显示文摘 | Clout NJ Tisi D Hohenester E | 2003 | Structure2003，11，2： | 1 |
| 11 | MNPBEM- A Matlab toolbox for the simulation of plasmonic nanoparticles显示文摘 | Hohenester U Trügler A | 2012 | Computer Physics Communications2012，183，2： | 1 |
| 12 | Laminins in basement membrane assembly显示文摘 | Hohenester E Yurchenco PD | 2013 | Cell Adh Migr2013，2013，7： | 1 |
| 13 | The crystal structure of a laminin G--like module reveals the molecular basis of alpha --dystroglycan binding to laminins, perlecan, and agrin显示文摘 | Hohenester E Tisi D Tahs JF | 1999 | Mol Cell1999，4，5： | 1 |
| 14 | A model of FAS1 domain 4 of the corneal protein beta(ig)-h3 gives a clearer view on corneal dystrophies显示文摘 | Clout NJ Hohenester E | 2003 | Mol Vis2003，9，： | 1 |
| 15 | Laminin network formation studied by reconstitution of ternary nodes in solution 显示文摘 | Purvis A Hohenester E | 2012 | J Biol Chem2012，2012，44： | 1 |
| 16 | Structural insight into Slit-Robo signalling显示文摘 | Hohenester E | 2008 | Biochem Soc Trans2008，36，25： | 1 |
| 17 | Laminins in basement membrane assembly显示文摘 | HOHENESTER E YURCHENCO P D | 2013 | Cell Adh Migr2013，7，1： | 1 |
| 18 | Mammalian collagen receptors 显示文摘 | Leitinger B Hohenester E | 2007 | Matrix Biol2007，26，3： | 1 |
| 19 | The biliary HCO3 - umbrella, a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosingcholangiop- athies显示文摘 | BEUERS U HOHENESTER S de BUY WENNIGER L J | 2010 | Hepatology2010，52，4： | 1 |
| 20 | Crystal structures of the net- work-forming short-arm tills of tile laminin β1 and y1 chains显示文摘 | Carafoli F Itussain S A Hohenester E | 2012 | PLoS One2012，7，7： | 1 |
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