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-beta 1 on this cytokine-induced expression, as TGF-beta has been shown to have immunosuppressive effects on EC. EC expressed MCP-1 mRNA and protein in response to TNF alpha, IFN gamma or IL-1beta, but not TGF-beta1. TGF-beta1 in cotreatment with either TNF alpha or IL-1beta, but not IFN gamma, significantly decreased MCP-1 mRNA and protein expression, as compared to TNF alpha or IL-1beta treatment alone. Pretreatment with TGF-beta had no effect on any cytokine-induced MCP-1 expression. TGF-beta had no effect on MCP-mRNA stability. Examination of TNF receptor expression by flow cytometry revealed that TNF alpha 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-beta alone decreased p75 surface expression and in cotreatment with TNF alpha, caused an additive decrease in p75 surface expression, as compared to TNF alpha treatment alone. Whereas mRNA expression for both receptors was increased with TNF alpha treatment, this was decreased with TGF-beta/TNF alpha cotreatment, as compared to TNF alpha treatment alone. Thus, the expression of TNF receptors was also down-modulated by TGF-beta. These findings indicate additional mechanisms by which TGF-beta exerts immunosuppressive properties on EC.