首页|Macrophage secretory products induce an inflammatory phenotype in hepatocytes

Macrophage secretory products induce an inflammatory phenotype in hepatocytes

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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 147patients 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-9attenuated 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.

MacrophagesHepatic fibrosisLipocalin-2Transforming growth factor-β1Matrix metalloproteinase-9

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

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Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane 4102,Queensland, Australia

Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane 4102, Queensland, Australia

Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane 4072, Queensland, Australia

Gethin P Thomas, Diamantina Institute, The University of Queensland, Brisbane 4102, Queensland, Australia

Centre for Liver Disease Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane 4102,Queensland, Australia Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane 4102, Queensland, Australia

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National Health and Medical Research Council of AustraliaQueensland Government's Smart State Health and Medical Research FundPrincess Alexandra Hospital Research and Development Foundation and The Sasakawa Foundation (Royal Children's Hospital,BrisbUnrestricted Education Grant from MSD (to Powell EE)Lions Medical Research Foundation Senior Research Fellowship (to Thomas GP)

APP 1003108

2012

10.3748/wjg.v18.i15.1732

世界胃肠病学杂志(英文版)
太原消化病研治中心

世界胃肠病学杂志(英文版)

SCI
影响因子：1.001
ISSN：1007-9327
年,卷(期)：2012.18(15)
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