Decrease of PECAM-1-gene-expression induced by proinflammatory cytokines IFN-Ú and IFN-» is reversed by TGF-Ø in sinusoidal endothelial cells and hepatic mononuclear phagocytes

Background and aim: 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. Methods and 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-? followed by an enhanced TGF-? protein level. As shown by Northern blot analysis and surface protein expression analysed by flow cytometry, IFN-?-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-?-treatment increased PECAM-1-expression. Additional administration of IFN-? to CCl4-treated rats and observations in IFN-?-/- mice confirmed the effect of IFN-? 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.Conclusion: 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-? in livers and may facilitate adhesion and transmigration of inflammatory cells. The up-regulation of PECAM-1-expression in SECs and MNPs after TGF-?-treatment suggests the involvement of PECAM-1 during the recovery after liver damage.