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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 | A new method for force-feeding larval fish显示文摘 | Rust M Hardy R W Stickney R R | 1993 | Aquaculture1993，116，： | 1 |
| 3 | Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1显示文摘 | Rust S Rosier M Funke H | | 0，，04： | 1 |
| 4 | The innovative moving bed biofilm reactor/solid contact reaeration process for secondary treatment of municipal wastewater显示文摘 | McCopy M Proctor R | 1998 | Water Environment Research1998，70，5： | 1 |
| 5 | The precise self as- sembly of individual carbon nanotubes using magnetic captu- ring and fluidic alignment 显示文摘 | ShimJ S Yun Y H Rust M J | 2009 | Nanotechnology2009，20，32： | 1 |
| 6 | Two-dimensional speed and optical risetime estimates for natural and triggered dart leaders显示文摘 | Mach D M Rust W D | 1997 | J Geophys Res1997，102，13： | 1 |
| 7 | Electrical structure in thunderstorm convective regions 1,Mesoscale convective system显示文摘 | Stolzenburg M W D Rust B F Smull | 1998 | J Geophys Res1998，103，14： | 1 |
| 8 | Overview of the southAfrican mechanistic pavement design method显示文摘 | Theyse L H De Beer M Rust C F | 2007 | Transportation Research Record2007，1539，： | 1 |
| 9 | Effects of chromium on growth and mineral nutrition of soybeans 显示文摘 | TURNER M A RUST R H | 1971 | Soil Sci Soc Am Proc1971，35，： | 1 |
| 10 | Photoelectric return-stroke velocity and peak current estimates in natural and triggered lightning显示文摘 | Mach D M Rust W D | 1989 | J Geophys Res1989，94，13： | 1 |
| 11 | Electrical structure in thunderstorm convective regions,2,Isolated storms显示文摘 | Stolzenburg M W D Rust T C Marshall | 1998 | J Geophys Res1998，103，14： | 1 |
| 12 | Monsegmental pedicle screw fixation for thoracolumbar brust fracture 显示文摘 | Steel T R Rust T M Fairhall J M | 2004 | J Bone Joint Surg Am2004，86，4： | 1 |
| 13 | Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1显示文摘 | Rust S Rosier M Funke H | 1999 | Nat Genet1999，22，35： | 1 |
| 14 | Electrical structure in thunderstorm convective regions,3,Synthesis显示文摘 | Stolzenburg M W D Rust T C Marshall | 1998 | J Geophys Res1998，103，14： | 1 |
| 15 | Methane produc- tion, consumption, and air-sea exchange in the open ocean: An Evaluation based on carbon isotopic ratios 显示文摘 | Holmes M E Sansone F J Rust T M | 2000 | Global Biogeo- chemical Cycles2000，14，1： | 1 |
| 16 | Microbial fin- gerprinting using matrix-assisted laser desorption ioni- zation time-of-flight mass spectrometry (MALDI-TOF MS) applications and challenges显示文摘 | Giebel R Worden C Rust S M | 2010 | Adv Appl Micro- biol2010，71，： | 1 |
| 17 | Learning,AMPA receptor mobility and synaptic plasticity depend on n-cofilin mediated actin dynamics显示文摘 | Rust MB Gurniak CB Renner M | 2010 | EMBO J2010，29，： | 1 |
| 18 | The carbon isotopic composition of atmospheric methane显示文摘 | Stevens C M Rust F E | 1982 | Journal of Geophysical Reasearch1982，87，： | 1 |
| 19 | Toxicity,uptake,and transfer efficiency of fipro-nil in western subterraneantermite (Isoptera : Rhinotermitidae ) 显示文摘 | SARAN R K RUST M K | 2007 | JEcon Entomol2007，100，2： | 1 |
| 20 | Effect of hexaflumuron on mortality of the Western subterranean termite (Isoptera:Rhinotermitidae) during and following exposure and movement of hexaflumuron in termite groups显示文摘 | HAAGSMA K A RUST M K | | 0，，06： | 1 |
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