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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 | Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-Like Receptor-2显示文摘 | Thimoteus Speer Lucia Rohrer Przemyslaw Blyszczuk Rukshana Shroff Kira Kuschnerus Nicolle Kr?nkel Gabriela Kania Stephen Zewinger Alexander Akhmedov Yi Shi Tina Martin Damir Perisa Stephan Winnik Maja F. Müller Urban Sester Gabriel Wernicke Andreas Jung U | 2013 | Immunity2013，，： | 2 |
| 3 | Growth and social security: the role of human capital显示文摘 | Alexander Kemnitz Berthold U Wigger | 2000 | European Journal of Political Economy2000，，4： | 2 |
| 4 | Estimating the sources and transport of nutrients in the Waikato River Basin, New Zealand 显示文摘 | Alexander R B Elliott A H Shankar U | 2002 | Water Resources Research2002，38，12： | 1 |
| 5 | Clinical rating systems for the ankle-hindfoot t midfoot t halliu and lesser toes显示文摘 | Kitaoka HB Alexander U Adelaar RS et ai | 1994 | Foot Ankle Int1994，15，7： | 1 |
| 6 | High strain rate compression response of carbon/epoxy laminate composites 显示文摘 | HOSUR M V ALEXANDER J VAIDY U K | 2001 | Composite Structures2001，52，34： | 1 |
| 7 | Effects of pulsed electric fields on cell membrances in real food systems显示文摘 | Alexander A U Volker H Dietrich K | 2000 | Innovative Food Science and Emerging Technologies2000，1，2： | 1 |
| 8 | Initial Steps of Photosynthetic Water Splitting by Associates of Porphyrin显示文摘 | Alexander V U | 2000 | Photochemistry and Photobiology A: Chemistry2000，130，1： | 1 |
| 9 | Effects of pulsed electric fields on cell membrances in real food systems 显示文摘 | Alexander Angersbach U Volker Heinz Dietrich Knorr | 2000 | Innovative Food Science & Emerging Technologies2000，1，2： | 1 |
| 10 | Comparison of two intr- amedullary nails for tibialotalocalcaneal fusion: anatomic and radio- graphic considerations 显示文摘 | Thomas M Sedastian U Alexander P | 2007 | Foot Ankle Int2007，5，： | 1 |
| 11 | Clinical systems for theankle-hindfoot, midfoot, hallux and lesser toes显示文摘 | Kitaoka HB Alexander U Adelaar RS | 1994 | Foot Ankle1994，15，7： | 1 |
| 12 | Clinical systems for theankle -hindfoot, midfoot,hallux and lesser toes 显示文摘 | Kitaoka HB Alexander U Adelaar RS | 1994 | Foot Ankle1994，15，7： | 1 |
| 13 | Anthracene-BODIPY Dyads as Fluorescent Sensors for Biocatalytic Diels-Alder Reac-tions显示文摘 | Alexander N Andrei Y K Nienhaus G U | 2010 | J Am Chem Soc2010，132，8： | 1 |
| 14 | Properties of Nd3+-doped and undoped tetragonal PbWO4,NaY (WO4)2,CaWO4,and undoped monoclinic ZnWO4 and CdWO4 as laser-active and stimulated Raman scattering-active crystals显示文摘 | ALEXANDER A K HANS J E KENICHI U | | 0，，21： | 1 |
| 15 | High strain rate compression response of carbon/epoxy laminate composites显示文摘 | HOSUR M V ALEXANDER J VAIDYA U K | 2001 | Composite Structures2001，52，3： | 1 |
| 16 | CONSTITUTIVELY PHOTOMORPHOGENIC1 is required for the UV-B response in Arabidopsis显示文摘 | Attila O Alexander B Zoltán M Agnieszka B Jean M Edward J O (E)va (A) Eberhard S Ferenc N Roman U | | 0，，08： | 1 |
| 17 | High strain rate compression response of carbon/epoxy laminate composites显示文摘 | Hosur M V Alexander J Vaidya U K | 2001 | Composite Structures2001，52，34： | 1 |
| 18 | Bacterial transport through nonhomogenous soil显示文摘 | Gannon J Mingelgrin U Alexander M Wagenet R.J | | 0，，： | 1 |
| 19 | Clinical rating systemsfor the ankle -hindfoot, midfoot, hallux, and lesser toes显示文摘 | Kitaoka HB Alexander U’Adelaar RS ef ai | 1994 | Foot AnkleInt1994，15，： | 1 |
| 20 | Histone deacetylase inhibitor trichostatin A induces global and gene - specific DNA demethylation in human cancer cell lines 显示文摘 | Jing - Ni O Je rome T Alexander U | 2007 | Biochem Pharmacol2007，73，： | 1 |
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