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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 | Biotransformation of S-Triaxine herbicides and related degradation products in liquid cultures by the white rot fungus Phanerochaete chrysosporium显示文摘 | CHRISTIAN M CHANTAL L MARCEL A T | 1997 | Pestie Sci1997，49，： | 1 |
| 3 | Lives Prod Sci显示文摘 | Rothschird M F Christian L L | 1988 | 19: 459-4711988，19，： | 1 |
| 4 | 查看详情显示文摘 | Torben S Thomas M Kjartan F Sφren L F Christian P | | 0，，： | 1 |
| 5 | Supported gold nanoparticles:In-depth catalyst characterization and application in hydrogenation and oxidation reactions显示文摘 | SABINE S MARTIN L CHRISTIAN M | 2002 | Catal Today2002，72，： | 1 |
| 6 | Targeting DNA Double-strand breaks with TAL effector nucleases显示文摘 | Christian M Cermak T Doyle E L | 2010 | Genetics2010，186，2： | 1 |
| 7 | A new approach to crystal- lographic orientation measurement for apatite fission track analysis, Effects of crystal morphology and implications for automation显示文摘 | Peternell M Kotdmann Fabian Wilson C J L Seiler Christian Gleadow A J W | 2009 | Chemical Geology2009，265，： | 1 |
| 8 | Efficient design and assembly of custom TALEN and other TAL effector based constructs for DNA targeting显示文摘 | Cermak T Doyle E L Christian M | 2011 | Nucleic Acids Research2011，39，12： | 1 |
| 9 | Sod reestablishment of five Kentucky bluegrass cultivars显示文摘 | Agnew M L Christians N E | 1992 | Journal of Production Agriculture1992，，5： | 1 |
| 10 | In-vitro culture of fertilized embryo sacs of maize: Zygotes and two-celled proembryos can develop into plants显示文摘 | Rafal Mòl Elisabeth Matthys-Rochon Christian Dumas | 1993 | Planta1993，，2： | 1 |
| 11 | Influence of fertilizer source and core cultivation on the growth of Kentucky bluegrass显示文摘 | Agnew M L Christians N E | 1993 | International Turfgrass Society Research Journal1993，，7： | 1 |
| 12 | Processing Snow for High Strength Roads and Runways 显示文摘 | RENEE M LANG GEORGE L BLAISDELL CHRISTIAN D'URSO | 1997 | Cold Regions Science and Technology1997，25，： | 1 |
| 13 | 显示文摘 | Yue Z R Christian L M James E | 2002 | Carbon2002，40，： | 1 |
| 14 | Where Do Developing Countries Go After Doha?An Analysis of WTO Positions and Potential Alliances显示文摘 | R B CHRISTIAN L M KIM | 2002 | Journal of World Trade2002，36，3： | 1 |
| 15 | Probabilistic flow pattern-based heat transfer correlation for condensing intermittent flow of refrigerants in smooth horizontal tubes 显示文摘 | van Rooyen E Christians M Liebenberg L Meyer J P | 2010 | International Journal of Heat and Mass Transfer2010，53，： | 1 |
| 16 | Effective primary isolation of wild-type Canine distemper virus in MDCK, MV1 Lu and Vero cells without nucleotide sequence changes within the entire haemagglutinin protein gene and in subgenomic sections of the fusion and phospho protein genes显示文摘 | John A Lednicky Thomas P Meehan Michael J Kinsel Jean Dubach Laura L Hungerford Nicolene A Sarich Kelley E Witecki Michael D Braid Casandra Pedrak Christiane M Houde | 2004 | Journal of Virological Methods2004，，2： | 1 |
| 17 | Sperm cells of Zea mays have a complex complement of mRNAs显示文摘 | Engel M L Annie C Christian D | 2003 | Plant Journal2003，34，5： | 1 |
| 18 | Atrial fibrillation in coronary artery disease显示文摘 | Sergiy L Christian M Volker K | 2000 | Inter J Cardio2000，72，： | 1 |
| 19 | Structure revision of medermycin lactoquinomycin a and of related C-8 glycosylated naphthoquinones 显示文摘 | Pierre M L Christophe M Christian P | 2002 | Org Lett2002，4，16： | 1 |
| 20 | Multi-rate optimizing control of simulated moving beds显示文摘 | Cristian G Christian L Marco M | 2010 | J of Process Control2010，20，4： | 1 |
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