title: Decrease of PECAM-1-gene-expression induced by proinflammatory cytokines IFN-gamma and IFN-alpha is reversed by TGF-beta in sinusoidal endothelial cells and hepatic mononuclear phagocytes.
abstract: OBJECTIVE
  The mechanisms of transmigration of inflammatory cells through the sinusoids are still poorly understood. This study aims to identify in vitro conditions (cytokine treatment) which may allow a better understanding of the changes in PECAM (platelet endothelial cell adhesion molecule)-1-gene-expression observed in vivo.
  
  
  RESULTS
  In this study we show by immunohistochemistry, that there is an accumulation of ICAM-1 (intercellular cell adhesion molecule-1) and ED1 positive cells in necrotic areas of livers of CCl4-treated rats, whereas there are few PECAM-1 positive cells observable. After the administration of CCl4, we could detect an early rise of levels of IFN-gamma followed by an enhanced TGF-beta protein level. As shown by Northern blot analysis and surface protein expression analysed by flow cytometry, IFN-gamma-treatment decreased PECAM-1-gene-expression in isolated SECs (sinusoidal endothelial cells) and mononuclear phagocytes (MNPs) in parallel with an increase in ICAM-1-gene-expression in a dose and time dependent manner. In contrast, TGF-beta-treatment increased PECAM-1-expression. Additional administration of IFN-gamma to CCl4-treated rats and observations in IFN-gamma-/- mice confirmed the effect of IFN-gamma on PECAM-1 and ICAM-1-expression observed in vitro and increased the number of ED1-expressing cells 12 h after administration of the toxin.
  
  
  CONCLUSIONS
  The early decrease of PECAM-1-expression and the parallel increase of ICAM-1-expression following CCl4-treatment is induced by elevated levels of IFN-gamma in livers and may facilitate adhesion and transmigration of inflammatory cells. The up-regulation of PECAM-1-expression in SECs and MNPs after TGF-beta-treatment suggests the involvement of PECAM-1 during the recovery after liver damage.
authors.affiliation: University of Göttingen, Department of Internal Medicine, Section of Gastroenterology and Endocrinology, Göttingen, Germany. kneubau@gwdg.de
authors.forename: Katrin
authors.initials: K
authors.lastname: Neubauer
authors.forename: Alexander
authors.initials: A
authors.lastname: Lindhorst
authors.forename: Kyrylo
authors.initials: K
authors.lastname: Tron
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ramadori
authors.forename: Bernhard
authors.initials: B
authors.lastname: Saile
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007155:Immunologic Factors / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D012157:Mononuclear Phagocyte System / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D016898:Interferon-alpha; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D002251:Carbon Tetrachloride