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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 | Relation between depression and anxiety in dystonic patients: implications for clinical management 显示文摘 | MORARU E SCHNIDER P WIMMER A | 2002 | Depress and Anxiety2002，16，3： | 1 |
| 3 | Topology-based interlocking of electrical substations显示文摘 | Kopainsky J Wimmer W Brand K P | 1986 | IEEE Transactions on Power Delivery1986，1，3： | 1 |
| 4 | Analysis of diflubenzuron by gas chromatography/mass spectrometry using deuterated diflubenzuron as internal standard显示文摘 | Wimmer M J Smith R R Jones J P | 1991 | Journal Agriculture Food Chemistry1991，39，2： | 1 |
| 5 | Comparison and evaluation of methods for liver segmentation from CT datasets显示文摘 | Heimann T van Ginneken B Styner MA Arzhaeva Y Aurich V Bauer C Beck A Becket C Beichel R Bekes G Bello F Binnig G Bischof H Bornik A Cashman PM Chi Y Cordova A Dawant BM Fidrich M Furst JD Furukawa D Grenacher L Hornegger J Kainmuller D Kitney RI Kobatake H Lamecker H Lange T Lee J Lennon B Li R Li S Meinzer HP Nemeth G Raicu DS Rau AM van Rikxoort EM Rousson M Rusko L Saddi KA Schmidt G Seghers D Shimizu A Slagmolen P Sorantin E Soza G Susomboon R Waite JM Wimmer A Wolf I | 2009 | IEEE Transactions on Medical Imaging2009，28，8： | 1 |
| 6 | Boron in plant biology 显示文摘 | BROWN P H BELLALOUI N WIMMER M A | 2002 | Plant Biology2002，4，： | 1 |
| 7 | Inhibition of in vitro VEGF expression and choroidal neovascularization by synthetic dendrimer peptide mediated delivery of a sense oligonucleotide显示文摘 | Marano R J Wimmer N Kearns P S | 2004 | Exp Eye Res2004，79，4： | 1 |
| 8 | Boron in plant biology显示文摘 | Brown P H Bellaloui N Wimmer M A | 2002 | Plant Biology2002，4，2： | 1 |
| 9 | Instant architecture显示文摘 | WONKA P WIMMER M SILLION F | 2003 | ACM Trans on Graphics2003，22，4： | 1 |
| 10 | Boron in plant biology 显示文摘 | Brown P H Bellaloui' N Wimmer M A | 2002 | Plant Biology2002，4，： | 1 |
| 11 | Treating patella in- stability in skeletally immature patients显示文摘 | Vavken P Wimmer M D Camathias C | 2013 | Arthroscopy2013，29，8： | 1 |
| 12 | Boron in plant biology显示文摘 | Brown P H Bellaloui N Wimmer M A | 2002 | Plant Biololgy2002，4，： | 1 |
| 13 | Mononucleotide and dinucleotide frequencies,and codon usage in poliovirion RNA显示文摘 | WIMMER E | 1981 | Nucleic Acids Res1981，9，23： | 1 |
| 14 | Instant achitecture 显示文摘 | WONKA P WIMMER M SILLION F | 2003 | ACM Trans Graphics2003，22，3： | 1 |
| 15 | Association Chlamydial infection with cerebrovascular disease 显示文摘 | Wimmer ML Sandmann SR Saikku P | 1996 | Stroke1996，27，12： | 1 |
| 16 | Determination of the reduction mechanism by temperature-programmed reduction: application to small iron oxide ( Fe2O3 ) particles 显示文摘 | Wimmers 0 J Anmldy P Moulijn J A | 1986 | J Phys Chem1986，90，7： | 1 |
| 17 | Association of chlamydial infection with cerebrovascular disease显示文摘 | Sandmann-strupp R Saikku P | 1996 | Stroke1996，27，12： | 1 |
| 18 | Delayed anterior spinal artery syndrome following posterior scoliosis correction显示文摘 | Stckl B Wimmer C Innerhofer P | 2005 | Eur Spine J2005，9，： | 1 |
| 19 | Parallel generation of multiple L-systems显示文摘 | Lipp M Wonka P Wimmer M | 2010 | Computers and Graphics2010，34，5： | 1 |
| 20 | Proteasome-dependent deg- radation of Daxx by the viral EIB-55K protein in human adenovirus- infected cells显示文摘 | Schreiner S Wimmer P Sirma H | 2010 | J Virol2010，84，14： | 1 |
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