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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 | Crowds:anonymity for web transactions显示文摘 | Reiter M K Rubin A D | 1998 | ACM Transactions on Information and System Security1998，1，1： | 2 |
| 3 | Post-stroke spasticity management with botulinum toxin injecting in the upper limb显示文摘 | Lagalla G Danni M Reiter F | 2000 | Am J Phy Med Rehab2000，79，： | 1 |
| 4 | Crowds:anonymity for web transactions显示文摘 | Reiter M K Rubin A D | 1998 | ACM Transactions on Information and System Security1998，1，1： | 1 |
| 5 | Crowds:anonymity for web transaction显示文摘 | REITER M K RUBIN A D | 1998 | ACM Transaction on Formation and System Security1998，1，1： | 1 |
| 6 | Intesive All-type therspy without local radiotherapy provides 90% EFS for children with T-cell lymphoblastic lymphoma:a BFM Group report显示文摘 | Reiter A Schrappe M Ludwig WD | | 0，，02： | 1 |
| 7 | Thiazolidinedione drugs block cardi- ac KATP channels and may increase propensity for ischaemic ven- trieular fibrillation in pigs显示文摘 | Lu L Reiter M J Xu Y | 2008 | Diabetologia2008，51，4： | 1 |
| 8 | Crowds: anonymity for Web transactions显示文摘 | REITER M K RUBIN A D | 1998 | ACM Transactions on Information and System Security1998，1，1： | 1 |
| 9 | Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000显示文摘 | Moricke A Zimmermann M Reiter A | 2010 | Leukemia2010，24，2： | 1 |
| 10 | Prophylactic actions of melatonin in oxidative neurotoxicity显示文摘 | Reiter R J Guerrero J M Escames G | 1997 | Ann N Y Acad Sci1997，825，2： | 1 |
| 11 | Melatonin and aging 显示文摘 | Karasek M Reiter BJ | 2002 | Neuroendocrinol Lett2002，，： | 1 |
| 12 | Botulinum tonin type A and short term electrical stimulation in treatment of upper limb flexor spasticity after stroke: arandomized, doubled-blind, placebo-controlled trial显示文摘 | Hesse S Reiter F Konrad M | 1998 | Clin Rehabil1998，12，： | 1 |
| 13 | Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy:results of trial ALL-BFM 90 显示文摘 | Schrappe M Reiter A Ludwig W D | 2000 | Blood2000，95，11： | 1 |
| 14 | Resilient Authentication Using Path Independence显示文摘 | M K Reiter S G Stubblebine | 1998 | IEEE Transactions on Computers1998，47，12： | 1 |
| 15 | Significance of melatonin in antioxidative defense system:reactions and products显示文摘 | Tan D X Lucien C M Reiter R J | 2000 | Biol Signal Recept2000，9，： | 1 |
| 16 | Anonymous Web transactions with crowds显示文摘 | REITER M K RUBIN A D | 1999 | Communications of the ACM1999，42，2： | 1 |
| 17 | Melatonin: reducing molecular pathology and dysfunction due to free radicals and associated reactants显示文摘 | Reiter BJ Tan DX Allegra M | 2002 | Neuroendocrinol Lett2002，，： | 1 |
| 18 | Rigorous analysis of arbitrarily shaped H-plane and E-plane discontinuities by a BCMM method显示文摘 | Reiter J M | 1995 | IEEE Trans Microwave Theory Tech1995，43，4： | 1 |
| 19 | Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unseleeted pediatric and adolescent patients enrolled in the trial ALL-BFM 95 显示文摘 | Moricke A Reiter A Zimmermann M | 2008 | Blood2008，111，9： | 1 |
| 20 | Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report显示文摘 | Reiter A Schrappe M Ludwig WD | 2000 | Blood2000，95，2： | 1 |
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