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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 | Carbon, nitrogen and oxygen implantation into TiN coatings显示文摘 | F Seidel H.-R Stock P Mayr | 1998 | Surface & Coatings Technology1998，，： | 2 |
| 3 | Rectal single dose immunization of mice with Escherichia coli 0157 : H7 bacterial ghosts induces efficient humoral and cellular immune responses and protects against the lethal heterologous challenge 显示文摘 | Mayr UB Kudela P Atrasheuskaya A | 2012 | Microb Biotechnol2012，5，2： | 1 |
| 4 | A randomized placebo- controlled trial of simethicone and cisapride for the treatment of pa- tients with functional dyspepsia 显示文摘 | Hohmann G Gschossmann J Mayr P | 2002 | Aliment Pharmacol Ther2002，16，： | 1 |
| 5 | The future of high-throughput screening 显示文摘 | MAYR LM FUERST P | 2008 | JBiomolScreen2008，13，6： | 1 |
| 6 | Bacterial ghosts as antigen delivery vehicles显示文摘 | MAYR U B WALCHER P AZIMPOUR C | 2005 | Adv Drug Deliv Rev2005，57，9： | 1 |
| 7 | Bacterial ghosts as antigen delivery vehicles显示文摘 | Mayr UB Walcher P Azimpour C | 2005 | Adv Drug Deliv Rev2005，57，9： | 1 |
| 8 | Antigen discovery and delivery of subunit vaccines by nonliving bacterial ghost vectors显示文摘 | WALCHER P MAYR U B AZIMPOUR-TABRIZI C | 2004 | Expert Rev Vaccines2004，3，6： | 1 |
| 9 | Insulin like growth factor Ⅰreceptor and PTEN protein expression in endometrial carcinoma:Correlation with bax and bcl-2 expression,microsatellite instability status,and outcome显示文摘 | Peiro G Lohse P Mayr D | 2003 | Am J Clin Pathol2003，120，1： | 1 |
| 10 | pAd5-Blue:direct ligation system for engineering recombinant adenovirus constructs显示文摘 | Moraes M P Mayr G A Grubman M J | 2001 | Biotechniques2001，31，： | 1 |
| 11 | TheSoz : A SKOS representa- tion of the thesaurus for the social sciences 显示文摘 | Zapilko B Sehaible J Mayr P | 2013 | Semantic Web2013，4，3： | 1 |
| 12 | Esche richia coli ghost production by expression o lysis gene E and staphylococcal nuclease 显示文摘 | HAIDINGER W MAYR U B SZOSTAK M P | 2003 | Mol Biotechnol2003，69，10： | 1 |
| 13 | Bacterial ghosts as novel effi- cient targeting vehicles for DNA delivery to thehuman monocyte - de- rived dendritic cells显示文摘 | Kudela P Paukner S Mayr U B | 2005 | J Immunother2005，28，2： | 1 |
| 14 | Characterization of a small porcine DNA virus 显示文摘 | Mayr A Bachmann P A Siegl G | 1968 | Arch of Virology1968，25，： | 1 |
| 15 | The structure of the nonamethylcyclopentyl cation显示文摘 | Kronja O Kohli T P Mayr H | 2000 | J Am Chem Soc2000，122，： | 1 |
| 16 | Reproducibility of femoral offset following short stem and straight stem total hip arthroplasty显示文摘 | von Roth P Perka C Mayr HO | 2014 | Orthopedics2014，37，7： | 1 |
| 17 | Meckil's diverticulum in children:a 20-year review显示文摘 | Mayr LB Stephane P | 1991 | J Pediatr Srug1991，26，： | 1 |
| 18 | An- tigen discovery and deliveryof subunit vaccines by nonliving bacterial ghost vectors 显示文摘 | Walcher P Mayr U B Azimpour-Tabrizi C | 2004 | Exp Rev Vac- cines2004，3，： | 1 |
| 19 | Bacterial ghosts as antigen delivery vehicles 显示文摘 | MAYR U B WALCHER P AZIMPOUR C | 2005 | Adv Drug Deliv Bev2005，57，9： | 1 |
| 20 | Antegrade scrotal sclerotherapy for treating primary varicocele in children 显示文摘 | Zaupa P Mayr J Hollwarth ME | 2006 | BJU Int2006，97，4： | 1 |
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