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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 | Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with thet(12:13)(p13:q12)显示文摘 | Chase A Reiter A Burci L | 1999 | Blood1999，93，3： | 1 |
| 3 | Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation 显示文摘 | Tan D X Manchester L C Reiter R J | 2000 | Free Radic Biol Med2000，29，11： | 1 |
| 4 | 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 |
| 5 | Oxidation Tuning in MCrN Coatings显示文摘 | Endrino J L Fox-Rabinovich G S Reiter A | 2007 | Surface & Coatings Technolo- gy2007，201，8： | 1 |
| 6 | PPARgamma controls cell proliferation and apoptosis in an RB -dependent manner显示文摘 | FAJAS L EGLER V REITER R | 2003 | Oncogene2003，22，27： | 1 |
| 7 | The retinoblastoma- histone deacetylase 3 complex inhibits PPARgarnma and adipocyte differentiation显示文摘 | Fajas L Egler V Reiter R | 2002 | Dev Cell2002，3，： | 1 |
| 8 | Dei ning pathways显示文摘 | De Bleser L Dep reitere R De Waele K | 2006 | Nurs M2006，14，7： | 1 |
| 9 | Pharma - cological actions of melatonin in oxygen radical pathophysiology 显示文摘 | Reiter R Tang L Garcia JJ | 1997 | Life Sci1997，60，： | 1 |
| 10 | The interaction of twoindenters in analogue experiments and implications for curved fold-and-thrust belt 显示文摘 | Reiter K Kukowski N Ratschbacher L | 2011 | Earth and Planetary Science Letters2011，302，12： | 1 |
| 11 | CA242 in comparisonwith established tumor markers in colorectal pancreatic and lung cancer 显示文摘 | Hasholzner L Stieber P Reiter W | 1999 | Anticancer Res1999，19，4： | 1 |
| 12 | Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger 显示文摘 | Tan D X Reiter R J Manchester L C | 2002 | Curr Topic Med Chem2002，2，： | 1 |
| 13 | Homophila: human dis- ease gcne cognates in Drosophila显示文摘 | Chien S Reiter L T Bier E | 2002 | Nucleic Acids Res2002，30，1： | 1 |
| 14 | Peripheral reproductive organ health and melatonin: ready for prime time 显示文摘 | Reiter R J Rosales-Corral S A Manchester L C | 2013 | IntJMolSci2013，14，4： | 1 |
| 15 | Melatonin in walnut: Influence on levels of melatonin and total antioxidant capacity of blood 显示文摘 | Reiter R J Manchester L C Tan D X | 2005 | Nutrition2005，21，9： | 1 |
| 16 | Significance of melatonin in antioxidative defense system: reactions and products 显示文摘 | Tan D X Manchester L C Reiter R J | 2000 | Biol Signals Recept2000，9，： | 1 |
| 17 | Multivariate analysis of the prognostic value of CEA and CA 19-9 serum levels in colorectal cancer 显示文摘 | Reiter W Stieber P Reuter L | 2000 | Anticancer Res2000，20，6： | 1 |
| 18 | Liquidity constraints on hospital investment when credit markets are tight显示文摘 | Reiter K L Wheeler J R C Smith D G | 2008 | Journal of Health Care Finance2008，35，1： | 1 |
| 19 | Population genetics with RAPD-PCR markers: the breeding structure of Aedes aegypti in Puerto Rico显示文摘 | Apostol B L Black W C Reiter P | 1996 | Heredity1996，76，4： | 1 |
| 20 | A review of the evidence supporting melatonin′s role as an antioxidant显示文摘 | Reiter RJ Melchiorri D Sewerynek E Poeggeler B Barlow-Walden L Chuang J | 1995 | J Pineal Res1995，18，1： | 1 |
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