Macrophage secretory products induce an inflammatory phenotype in hepatocytes

查看全文 作　　者：Michelle [1]Melino;Victoria L [1]Gadd;Gene V [1]Walker;Richard [1,2]Skoien;Helen D [1]Barrie;Dinesh [1]Jothimani;Leigh [2]Horsfall;Alun [3]Jones;Matthew J [3]Sweet;Gethin P [4]Thomas;Andrew D [1]Clouston;Julie R [1]Jonsson;Elizabeth E [1,2]Powell

机构地区：[1]Centre for Liver Disease Research,School of Medicine,The University of Queensland,Princess Alexandra Hospital,Brisbane 4102,Queensland,Australia;[2]Department of Gastroenterology and Hepatology,Princess Alexandra Hospital,Brisbane 4102,Queensland,Australia;[3]Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre,The University of Queensland,Brisbane 4072,Queensland,Australia;[4]Diamantina Institute,The University of Queensland,Brisbane 4102,Queensland,Australia

出　　处：《World Journal of Gastroenterology》索引2012年第18卷第15期,共13页

基　　金：Supported by The National Health and Medical Research Council of Australia,No.APP1003108;the Queensland Government’s Smart State Health and Medical Research Fund;The Princess Alexandra Hospital Research and Development Foundation;The Sasakawa Foundation(Royal Children’s Hospital,Brisbane);an Unrestricted Education Grant from MSD(to Powell EE);a Lions Medical Research Foundation Senior Research Fellowship(to Thomas GP) 摘　　要：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. 关键词：细胞分泌肝细胞诱导 mRNA表达 HepG2细胞丙型肝炎病毒转化生长因子 MMP-9

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Macrophage secretory products induce an inflammatory phenotype in hepatocytes

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