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| 1 | Macrophage secretory products induce an inflammatory phenotype in hepatocytes显示文摘AIM:To investigate the influence of macrophages on hepatocyte phenotype and function.METHODS:Macrophages were differentiated from THP-1 monocytes via phorbol myristate acetate stimulation and the effects of monocyte or macrophageconditioned medium on HepG2 mRNA and protein expression determined.The in vivo relevance of these findings was confirmed using liver biopsies from 147 patients with hepatitis C virus(HCV)infection.RESULTS:Conditioned media from macrophages,but not monocytes,induced a transient morphological change in hepatocytes associated with upregulation of vimentin(7.8±2.5-fold,P=0.045)and transforming growth factor(TGF)-β1(2.6±0.2-fold,P<0.001)and downregulation of epithelial cadherin(1.7±0.02-fold,P=0.017)mRNA expression.Microarray analysis revealed significant upregulation of lipocalin-2(17-fold,P <0.001)and pathways associated with inflammation,and substantial downregulation of pathways related to hepatocyte function.In patients with chronic HCV,realtime polymerase chain reaction and immunohistochemistry confirmed an increase in lipocalin-2 mRNA(F0 1.0 ±0.3,F1 2.2±0.2,F2 3.0±9.3,F3/4 4.0±0.8,P= 0.003)and protein expression(F1 1.0±0.5,F2 1.3± 0.4,F3/4 3.6±0.4,P=0.014)with increasing liver injury.High performance liquid chromatography-tandem mass spectrometry analysis identified elevated levels of matrix metalloproteinase(MMP)-9 in macrophageconditioned medium,and a chemical inhibitor of MMP-9 attenuated the change in morphology and mRNA expression of TGF-β1(2.9±0.2 vs 1.04±0.1,P<0.001) in macrophage-conditioned media treated HepG2 cells.In patients with chronic HCV infection,hepatic mRNA expression of CD163(F0 1.0±0.2,F1/2 2.8±0.3,F3/4 5.3±1.0,P=0.001)and MMP-9(F0 1.0±0.4,F1/2 2.8±0.3,F3/4 4.1±0.8,P=0.011)was significantly associated with increasing stage of fibrosis.CONCLUSION:Secreted macrophage products alter the phenotype and function of hepatocytes,with increased expression of inflammatory mediators,suggesting that hepatocytes actively participate in liver injury. | Michelle Melino Victoria L Gadd Gene V Walker Richard Skoien Helen D Barrie Dinesh Jothimani Leigh Horsfall Alun Jones Matthew J Sweet Gethin P Thomas Andrew D Clouston Julie R Jonsson Elizabeth E Powell | 2012 | World Journal of Gastroenterology2012，18，15： | 3 |
| 2 | Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration显示文摘AIM:To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype(SASP).METHODS:Hydrogen peroxide treatment was used to induce senescence in the human Hep G2 hepatocyte cell line.Senescence was confirmed by cytochemical staining for a panel of markers including Ki67,p21,heterochromatin protein 1β,and senescence-associated-β-galactosidase activity.Senescent hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction(q PCR),and conditioned media was used in proteomic analyses,a human chemokine protein array,and cell migration assays to characterise the composition and function of the hepatocyte SASP.RESULTS:Senescent hepatocytes induced classical markers of senescence(p21,heterochromatin protein1β,and senescence-associated-β-galactosidase activity);and downregulated the proliferation marker,Ki67.Hepatocyte senescence induced a 4.6-fold increase in total secreted protein(P=0.06)without major alterations in the protein profile.Senescence-induced genes were identified by microarray(Benjamini Hochbergcorrected P<0.05);and,consistent with the increase in secreted protein,gene ontology analysis revealed a significant enrichment of secreted proteins among inducible genes.The hepatocyte SASP included characteristic factors such as interleukin(IL)-8 and IL-6,as well as novel components such as SAA4,IL-32and Fibrinogen,which were validated by q PCR and/or chemokine protein array.Senescent hepatocyteconditioned medium elicited migration of inflammatory(granulocyte-macrophage colony stimulating factor,GM-CSF-derived),but not non-inflammatory(CSF-1-derived)human macrophages(P=0.022),which could contribute to a pro-inflammatory microenvironment in vivo,or facilitate the clearance of senescent cells.CONCLUSION:Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis. | Katharine M Irvine Richard Skoien Nilesh J Bokil Michelle Melino Gethin P Thomas Dorothy Loo Brian Gabrielli Michelle M Hill Matthew J Sweet Andrew D Clouston Elizabeth E Powell | 2014 | World Journal of Gastroenterology2014，20，47： | 2 |
| 3 | The global burden of iron overload显示文摘 | Marnie J. Wood Richard Skoien Lawrie W. Powell | 2009 | Hepatology International2009，，3： | 1 |
| 4 | Fatty acids induce hcpatocyte senescene in vitro: implications for pathogenesis in NASH显示文摘 | SKOIEN R POWELL EE MELINO M | 2010 | Hepatology2010，52，1： | 1 |
| 5 | Colour pop-out in infant response to visual array显示文摘 | CATHERWOOD D SKOIEN P HOLT C | 1996 | British Jounal of Developmental Psychology1996，，14： | 1 |
| 6 | The global burden of iron overload显示文摘 | Marnie J. Wood Richard Skoien Lawrie W. Powell | 2009 | Hepatology International2009，，3： | 1 |
| 7 | Immersion coating of pellet cores consisting of chitosan and calcium intended for colon drug delivery显示文摘 | Hiorth Marianne Skoien Terje Sande Sverre Arne | 2010 | European Journal of Pharmaceutics and Biopharmaceutics2010，75，： | 1 |
| 8 | Awareness and opinions of non‐alcoholic fatty liver disease by hospital specialists显示文摘 | C.‐J. Bergqvist R. Skoien L. Horsfall A. D. Clouston J. R. Jonsson E. E. Powell | 2013 | Intern Med J2013，，3： | 1 |
| 9 | The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease显示文摘 | Gadd V L Skoien R Powell E E | 2014 | Hepatology2014，59，4： | 1 |
| 10 | The global burden of iron over-load 显示文摘 | Wood MJ Skoien R Powell LW | 2009 | Hepatol Int2009，3，3： | 1 |
| 11 | Characteristic space scales and timescales in hydrology 显示文摘 | SKOIEN J O BLOSCHL G WESTERN A W | 2005 | Water Resources Research2005，39，10： | 1 |
| 12 | The global burden of iron over- load显示文摘 | Wood MJ Skoien R Powell LAW | 2009 | Hepatol Int2009，3，3： | 1 |
| 13 | Heterogeneity of fibrosis patterns in non‐alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways显示文摘 | Richard Skoien Michelle M. Richardson Julie R. Jonsson Elizabeth E. Powell Elizabeth M. Brunt Brent A. Neuschwander‐Tetri Prithi S. Bhathal John B. Dixon Paul E. O’Brien Herbert Tilg Alexander R. Moschen Ulrich Baumann Rachel M. Brown Richard T. Couper Ni | 2013 | Liver Int2013，，4： | 1 |
| 14 | Awareness and opinions of non‐alcoholic fatty liver disease by hospital specialists显示文摘 | C.‐J. Bergqvist R. Skoien L. Horsfall A. D. Clouston J. R. Jonsson E. E. Powell | 2013 | Intern Med J2013，，3： | 1 |
| 15 | The global burden of iron overload显示文摘 | Wood MJ Skoien R Powell LW | 2009 | Hepatol Int2009，3，43： | 1 |
| 16 | Heterogeneity of fibrosis patterns in non - alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways 显示文摘 | Skoien R Richardson MM Jonsson JR | 2013 | Liver International2013，33，4： | 1 |
| 17 | The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease显示文摘 | Gadd VL Skoien R Powell EE | 2014 | Hepatology2014，59，4： | 1 |
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