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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 | Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and or paracrine substance显示文摘 | Carrillo-Vieo A Cairo JR Abreu P Lardone PJ Garcia-Maurino S Reiter R J | 2004 | FASEB J2004，18，3： | 1 |
| 3 | A review of the evidence supporting melatonin′s role as an antioxidant显示文摘 | Reiter R Melchiorri P Sewerynek E | 1995 | J Pineal Rea1995，18，1： | 1 |
| 4 | Treatment of flow-through trout aquaculture effluents in a constructed wetland显示文摘 | Sindilariu P D Schulz C Reiter R | 2007 | Aquaculture2007，270，1234： | 1 |
| 5 | Role of homeostatic chemokine and sphingosine-1-phosphate receptors in the organization of lymphoid tissue显示文摘 | Muller G Reiterer P Hopken UE | 2003 | Ann NY Acad Sci2003，987，： | 1 |
| 6 | Alternative pathways to prostate carcinoma activate prostate stem cell antigen expression 显示文摘 | Dubey P Wu H Reiter R E | 2001 | Cancer Res2001，61，： | 1 |
| 7 | Introduction and establishment of Aedes (Stegomyia) albopictus skuse (Diptera: Culicidae) in Albania显示文摘 | Adhami J Reiter P | 1998 | J Am Mosq Control Assoc1998，14，3： | 1 |
| 8 | Robot-assisted versus conventional laparoscopic fundoplication: Short-term outcome of a pilot randomized controlled trial显示文摘 | Muller-Stich B P Reiter M A Wente M N | 2007 | Surgical En- doscopy and Other Interventional Techniques2007，21，10： | 1 |
| 9 | 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 |
| 10 | Mutagen sensitivity and DNA repair of the EGFR gene in oropharyngeal cancer 显示文摘 | Reiter M Welz C Baumeister P | 2010 | Oral Oncol2010，46，7： | 1 |
| 11 | Role of homeostatic che- mokine and sphingosine-1-phosphate receptorsin the organization of lymphoid tissue 显示文摘 | Muller G Reiterer P Hopken UE | 2003 | Ann N Y Acad Sci2003，987，： | 1 |
| 12 | Visualizing generalized 3x+1 function dynamics显示文摘 | Dumont Jeffrey P Reiter Clifford A | 2001 | Computers & Graphics2001，25，5： | 1 |
| 13 | Discovery of new markers of cancerthrough serial analysis of gene expression : prostate stem cell antigen overexpressed in pancreatic adenocarcinoma显示文摘 | Argani P Robert C Reiter E | 2001 | Cancer Res2001，61，11： | 1 |
| 14 | False data injection attacks against state estimation in electric power grids显示文摘 | Liu Y Ning P Reiter M K | 2011 | ACM Transactions on Information and System Security2011，14，1： | 1 |
| 15 | 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 |
| 16 | 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 |
| 17 | Visualizing generalized 3x+1 function dynamics 显示文摘 | Dumont J P Reiter C A | 2001 | Computers & Graphics2001，25，5： | 1 |
| 18 | Alternative pathways to prostate carcinoma activate prostate stem cell antigen expression显示文摘 | Dubey P Wu H Reiter RE | 2001 | Cancer Res2001，61，8： | 1 |
| 19 | A Security Architecture for Fault-Tolerant Systems 显示文摘 | M K Reiter K P Birman R van Rennesse | 1994 | ACM Transactions on Computer Systems1994，12，4： | 1 |
| 20 | Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma显示文摘 | Argani P Rosty C Reiter RE | 2001 | Cancer Res2001，61，11： | 1 |
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