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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 | Photo-toxic maeu-lopathy after arc welding:value of multifocal ERG显示文摘 | Denk PO Kretsehmann U Gonzalez J | 1997 | Klin Mon-bl Augenheilkd1997，211，： | 1 |
| 3 | The IKK- 2/I kappa B alpha/NF- kappa B pathway plays a key role in the regulation of CCR3 and eotaxin - 1 in fibroblasts :a critical link to dermatitis in I kappa B alpha - deficient mice 显示文摘 | Huber M A Denk A Peter R U | 2002 | J Biol Chem2002，277，2： | 1 |
| 4 | Chemically defined medium determines the differential potency of renal stem cells显示文摘 | DENK L DE VRIS U | 2007 | Biotech J2007，2，8： | 1 |
| 5 | Genetic complementation to non-tumourigenicity in cervical-carcinoma cells correlates with alterations in AP-1 composition显示文摘 | Soto U Denk C Finzer P | 2000 | Int J Cancer2000，86，6： | 1 |
| 6 | Genetic complementation to non-tumourigenicity in cervical-carcinoma cells correlates with alterations in AP-1 composition显示文摘 | Soto U Denk C Finzer P | 2000 | Cancer2000，86，6： | 1 |
| 7 | The spectrum of fungal allergy显示文摘 | Simon-Nobbe B Denk U P(o)ll V | | 0，，01： | 1 |
| 8 | The spectrum of fungal allergy显示文摘 | Simon-Nobbe B Denk U PSll V | 2008 | Int Arch Allergy Immunol2008，145，1： | 1 |
| 9 | Down-regulation of the organic cation transporter 1 of rat liver in obstructive chole- stasis显示文摘 | Denk G U Soroka C J Mennone A | 2004 | Hepatology2004，39，5： | 1 |
| 10 | The spectrum of lungal allergy 显示文摘 | SIMON-NOBBE B DENK U POLL V | 2008 | International Archives of Allergy & Immunology2008，145，1： | 1 |
| 11 | NADP-dependent mannitol dehydrogenase,a major allergen of Cladosporium herbarum显示文摘 | Simon-Nobbe B Denk U Schneider P B | 2006 | J Biol Chem2006，281，16： | 1 |
| 12 | Chemically defined medium determines the differential potency of renal stem cells显示文摘 | Hu K Denk L de Vries U | 2007 | Biotechnol J2007，2，8： | 1 |
| 13 | NADP-depend- ent mannitol dehydrogenase, a major allergen of Cladosporium herbarum 显示文摘 | Simon-Nobbe B Denk U Schneider PB | 2006 | J Biol Cbem2006，281，16： | 1 |
| 14 | Ahernaria alter- nata NADP-dependent mannitol dehydrogenase is an important fungal allergen显示文摘 | Schneider PB Denk U Breitenbach M | 2006 | Clin Exp Allergy2006，36，12： | 1 |
| 15 | A comparison of gene expression in mouse liver and kidney in obstructive cholestasis utilizing high-density oligonucleotide microarray technology显示文摘瞄准:用微数组技术在大量基因表示上估计妨碍的胆汁郁积的效果。方法:男 C57BL/6J 老鼠经历了胆总管结扎(BDL ) 并且与对美联储假冒操作控制被匹配。在 7 d 以后,动物被牺牲,全部的 RNA 从肝和肾被孤立。从每纸巾的 RNA 的相等的数量为每个组和 hybridized 被分享到包含 12488 个探针集合的一个总数的 Affymetrix GeneChip MG-U74Av2。数据分析用 GeneSpring 6.0 软件被执行。北分析和免疫荧光被用于确认。结果:在假冒操作和 BDL 老鼠,而 49 和 51% 分别地在肾被表示, 12488 中的 44 个和 50% 基因在肝被表示。在有 GeneOntology 注解的 BDL, 265 肝和 112 肾基因以后的七天是起来调整的, 113 肝和 36 肾基因与假冒操作控制比较是下面调整的。许多基因通常在代表的纸巾和新陈代谢相关的基因被调整最大的机能簇。结论:后面的 BDL,微数组分析在肝和肾揭示大量基因改变。 | Gerald U Denk Shi-Ying Cai Wen-Sheng Chen Aiping Lin Carol J Soroka James L Boyer | 2006 | World Journal of Gastroenterology2006，12，16： | 0 |
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