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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 | Results of a Summer Academy to Increase Minority Student Access to Allied Health and Other Health Professions显示文摘 | Thomson W A Denk J P Miller L M | 1991 | J Allied Health1991，21，1： | 1 |
| 3 | Tuning of the photoinduced charge transfer process in donor-acceptor double-cable copolymers 显示文摘 | Luzzati S Mozer A Denk P | 2003 | Synth Met2003，139，3： | 1 |
| 4 | Transanal Endoscopic Microsurgical Platform for Natural Orifice Surgery显示文摘 | Denk P M Swanstrom L L Whiteford MH | 2008 | Gastrointest Endosc2008，68，5： | 1 |
| 5 | Two-photon imaging to a depth of 1 000 microns in living brains by use of a Ti : Al2O3 regenerative amplifier 显示文摘 | Theer P Hasan MT Denk W | 2003 | Opt Lett2003，28，： | 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 | Int J Cancer2000，86，6： | 1 |
| 7 | Loss of maspin expression contributes to a more invasive potential in malignant melanoma显示文摘 | Denk A E Bettstetter M Wild P J | | 0，，02： | 1 |
| 8 | Highly efficient in- verted organic photovoltaics using solution based titaniumoxide as electron selective contact 显示文摘 | Waldauf C Morana M Denk P | 2006 | Applied Physics Letters2006，89，25： | 1 |
| 9 | 显示文摘 | Mozer A J Denk P Scharber M C | 2005 | Synthetic Metals2005，153，： | 1 |
| 10 | Lack of Pseudomelanosis coli in colonic adenomas suggests different pathways of apoptotic bodies in normal and neoplastic colonic mucosa 显示文摘 | Regitnig P Denk H | 2000 | Virchows Arch2000，436，6： | 1 |
| 11 | 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 |
| 12 | Inflammatory and apoptotic alterations in serum and injured tissue after experimen?tal poly trauma in mice: distinct early response com?pared with single trauma or 'double-hit' injury显示文摘 | Weckbach S Hohmann C Braumueller S Denk S Klohs B Stahel P F | 2013 | J Trauma Acute Care Surg2013，74，： | 1 |
| 13 | Lack of Pseudomelanosis coli in colonicadenomas suggests different pathways of apoptotic bodies in normaland neoplastic colonic mucosa 显示文摘 | Regitnig P Denk H | 2000 | Virchows Arch2000，，： | 1 |
| 14 | Long- lived photoinduced charge separation for solar cell applications in phthaloeyanine-fulleropyrrolidine dyad thin films 显示文摘 | LOI M A DENK P HOPPE H | 2003 | Journal of Materials Chemis- try2003，13，： | 1 |
| 15 | Effect of cytokines on regulation of the production of transforming growth factor beta-1in cultured human Tenon's capsule fibro-blasts显示文摘 | DENK P O ROTH EICHHORN S GRESSNER A M | 2000 | Eur J Ophthalmol2000，10，2： | 1 |
| 16 | Long lived photoinduced charge separation for solar ceil applications in phthalocya- nine-fulleropyrrolidine dyad thin films显示文摘 | Loi A Denk P Hoppe H | 2003 | J Mater Chem2003，13，70： | 1 |
| 17 | etc Novel regiospecific MDMO-PPV polymers with improved charge transport properties for bulk heterojunction solar cells显示文摘 | Mozer A J Denk P Scharber M C | 2005 | Synthetic Metals2005，153，： | 1 |
| 18 | Lack of Pseudomelanosis coli in colonic adenomas suggests different pathways of apoptotic bodies in normal and neoplastic colonic mucosa显示文摘 | Regitnig P Denk H | 2000 | Virchows Arch2000，436，6： | 1 |
| 19 | Development and validation of a new generation of flexible endoscope for NOTES 显示文摘 | Swanstrom L Swain P Denk P | 2009 | Surg Innov2009，16，2： | 1 |
| 20 | The spectrum of fungal allergy显示文摘 | Simon-Nobbe B Denk U P(o)ll V | | 0，，01： | 1 |
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