TGF-beta downmodulates cytokine-induced monocyte chemoattractant protein (MCP)-1 expression in human endothelial cells. A putative role for TGF-beta in the modulation of TNF receptor expression

The expression of chemokines, including monocyte chemoattractant protein (MCP)-1, by many cell types contributes to the pathogenesis of inflammatory diseases. We examined MCP-1 expression in human umbilical vein endothelial cells (EC) following cytokine treatment. We specifically compared the effect of TGF-β1 on this cytokine-induced expression, as TGF-β has been shown to have immunosuppressive effects on EC. EC expressed MCP-1 mRNA and protein in response to TNFα, IFNγ or IL-1β, but not TGF-β1. TGF-β1 in cotreatment with either TNFα or IL-1β, but not IFNγ, significantly decreased MCP-1 mRNA and protein expression, as compared to TNFα or IL-1β treatment alone. Pretreatment with TGF-β had no effect on any cytokine-induced MCP-1 expression. TGF-β had no effect on MCP-1 mRNA stability. Examination of TNF receptor expression by flow cytometry revealed that TNFα treatment caused a decrease of p75 expression on the cell surface. The p55 receptor was not detected at the cell surface, but was localized intracellularly by confocal microscopy. Treatment of EC with TGF-β alone decreased p75 surface expression and in cotreatment with TNFα, caused an additive decrease in p75 surface expression, as compared to TNFα treatment alone. Whereas mRNA expression for both receptors was increased with TNFα treatment, this was decreased with TGF-β/TNFα cotreatment, as compared to TNFα treatment alone. Thus, the expression of TNF receptors was also down-modulated by TGF-β. These findings indicate additional mechanisms by which TGF-β exerts immunosuppressive properties on EC.