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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 | Solitary keratoacanthoma:a self-healing proliferation that frequently becomes malignant显示文摘 | Sanchez Yus E Simon P Requena L | 2000 | Am J Dermatopathol2000，22，4： | 2 |
| 3 | Electrode compositions for carbon power supercapacitors显示文摘 | BONNEFOI L SIMON P FAUVARQUE J F | 1999 | J Power Sources1999，80，： | 1 |
| 4 | Electrode surface treatment and electrochemical impedance spectroscopy study on carbon/carbon supercapacitors 显示文摘 | TABERNA P L SIMON P | 2006 | Applied Physics2006，82，4： | 1 |
| 5 | Impacts of land use conflicts on riverine ecosystems 显示文摘 | Renato F Valle Junior Simone G P Varandas Femando A L Pacheco | 2014 | Land Use Policy2014，43，： | 1 |
| 6 | Procalcitonin and C--reactive protein as markers of bacterial infection in critically ill children at onset of systemic inflammatory response syndrome 显示文摘 | Simon L Saint-- Louis P Amre DK | 2008 | Pediatr CritCare Med2008，9，4： | 1 |
| 7 | Outcomed and clinicopa thologic variables associated with late recurrence after nephrectomy fkr localiged Renal cell carcinoma显示文摘 | SIMON P K CHRISTOPHER J M BRADLEY C L | 2011 | Urology2011，78，5： | 1 |
| 8 | Studies and characterisations of various activated carbons used for carbon/carbon supercapacitors 显示文摘 | Gamby J Taberna P L Simon P | 2001 | J Power Sources2001，101，1： | 1 |
| 9 | Electrochemical characteristics and impedance spectroscopy studies of carbon-carbon supercapacitors显示文摘 | TABERNA P L SIMON P FAUVARQUE J F | 2003 | J Electrochem Soc2003，150，3： | 1 |
| 10 | Integrated uniplanar transition for linearly tapered slot antenna 显示文摘 | Simons R N Dib N I Lee R Q Katehi L P B | 1995 | IEEE Transactions on Antennas and Propagation1995，43，9： | 1 |
| 11 | Modification of Al current collector/active material interface for power improvement of electrochemical capacitor electrodes 显示文摘 | PORTET C TABERNA P L SIMON P | 2006 | The Electrochemical Society2006，153，4： | 1 |
| 12 | De- velopment of polymer-ceramic composites for improved fire resistance显示文摘 | HANU L G SIMON G P MANSOURI J | 2004 | J Mater Process Technol2004，153，： | 1 |
| 13 | Copper-Zinc-Cobalt-Aluminium-Chromium Hydroxycarbonates and Mixed Oxides显示文摘 | Simone G Mariano L J Piero P | 1996 | J SolidState Chem1996，122，： | 1 |
| 14 | Polyethylene made with in situ supported ni-diimine/SMAO: replication phenomenon and effect of polymerization conditions on polymer microstructure and morphology 显示文摘 | Simon L C Patel H Soares J B P | 2001 | Macromol Chem Phys2001，202，17： | 1 |
| 15 | Processing and characterization of PbTiO3 thick films on alumina substrates显示文摘 | Simon L Ledren S Gonnand P | 2002 | Journal of Electroceramics2002，8，： | 1 |
| 16 | AFLP-based fine mapping of the Mlo gene to a 30-kb DNA segment of the barley genome显示文摘 | VANDER L T DIERGAARDE P | 1997 | Genetics1997，44，： | 1 |
| 17 | Effect of paraox- onase I polymorphism oll clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction 显示文摘 | Simon T Steg P G Becquemont L | 2011 | Clinical Pharmacology & Therapeutics2011，90，4： | 1 |
| 18 | Studies and eharacterisations of various activated carbons used for carbon/carbon supercapacitors 显示文摘 | Gamby J Taberna P L Simon P | 2001 | Journal of Power Sources2001，101，1： | 1 |
| 19 | Multielectrode prismatic power prototype carbon / earbon super-capacitors 显示文摘 | BONNEFOI L SIMON P FAUVARQUE J F | 1999 | Power Sources1999，83，： | 1 |
| 20 | Live birth after autograft of ovarian tissue cryopreserved during childhood显示文摘 | Demeestere I Simon P Dedeken L | 2015 | Hum Reprod2015，30，9： | 1 |
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