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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 | Serine and glycine metabolism in cancer显示文摘 | Ivano Amelio Francesca Cutruzzolá Alexey Antonov Massimiliano Agostini Gerry Melino | 2014 | Trends in Biochemical Sciences2014，，： | 2 |
| 4 | Influence of the thermal energy storage on the profitability of micro-CHP systems for residential building applications显示文摘 | Barbieri E S Melino F Morini M | 2012 | Appl Energy2012，，97： | 1 |
| 5 | The corni- fled envelope:a model of cell death in the skin 显示文摘 | Candi E Schmidt R Melino G | 2005 | Nature Reviews Molecular Cell Bidogy2005，6，4： | 1 |
| 6 | 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 |
| 7 | Performance prediction of micro-CHP systems using simple virtual operating cycles显示文摘 | M. Bianchi A. De Pascale F. Melino A. Peretto | 2013 | Applied Thermal Engineering2013，，： | 1 |
| 8 | Cell death pathology: Perspective for human diseases 显示文摘 | Agostini M Tucci P Melino G | 2011 | Biochem Bioph Res Co2011，414，3： | 1 |
| 9 | The impact of p53 and p73 on aneuploidy and cancer显示文摘 | Tomasini R Mak T W Melino G | 2008 | Trends Cell Biol2008，18，5： | 1 |
| 10 | p73: in silico evi dence for a putative third promoter region显示文摘 | Sayan A E Rossi M Melino G Knight R A | 2004 | Biochem Biophys Res Commun2004，313，： | 1 |
| 11 | Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity显示文摘 | Salah Z Melino G Aqeilan RI | 2011 | Cancer Res2011，71，5： | 1 |
| 12 | p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation显示文摘 | Bernassola F Ranalli M | 2004 | J Biol Chem2004，279，9： | 1 |
| 13 | Recognition of p63 by the E3 ligase ITCH : effect of an ectodermal dysplasia mutant显示文摘 | Bellomaria A Barbato G Melino G eta | 2010 | Cell Cycle2010，9，： | 1 |
| 14 | 1363 is a suppressor of tumorigenesis and metastasis interacting with mutant P53 显示文摘 | Melino G | 2011 | Cell Death Differ2011，18，9： | 1 |
| 15 | Histatins: salivary peptides with copper (11)- and zinc (11)-binding motifs: perspectives for biomedical applications显示文摘 | Melino S Santone C Di Nardo P | 2014 | FEBS J2014，281，3： | 1 |
| 16 | Pricing foreign currency options with stochastic volatility显示文摘 | Melino A Turnbull S M | | 0，，： | 1 |
| 17 | The cornified envelope:a model of cell death in the skin 显示文摘 | Candi E Schmidt R Melino G | 2005 | Nat Rev Mol Cell Biol2005，6，4： | 1 |
| 18 | Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein显示文摘 | Candi E Melino G Mei G | 1995 | J Biol Chem1995，270，26： | 1 |
| 19 | p73 induces apoptosis via PUMA transaetivation and Bax mitochondrial translocation 显示文摘 | Melino G Bernassola F Ranalli M Yee K Zong W X Corazzari M | 2004 | J Biol Chern2004，279，： | 1 |
| 20 | p53:25 years of research and more questions to answer显示文摘 | Bourdon J C Laurenzi V D Melino G | | 0，，04： | 1 |
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