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.

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-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.

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-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.