Endotoxin induces downregulation of tumor necrosis factor receptors on circulating monocytes and granulocytes in humans

Abstract

Leukocytes rapidly lose their surface receptors for tumor necrosis factor (TNF) after exposure to various stimuli in vitro. To assess the effect of endotoxin on cellular TNF receptors in humans in vivo, binding of biotinylated TNF to circulating monocytes and granulocytes was determined by fluorescence-activated cell sorter analysis in six healthy subjects after intravenous injection of endotoxin (lot EC-5, 20 U/kg). Endotoxin administration was associated with a transient decrease in monocyte TNF receptors, reaching a nadir after 2 hours (P < .0001), and a more sustained decrease in granulocyte TNF receptors (P < .001). Although the decrease in cellular TNF receptors coincided with increases in soluble TNF receptors types I and II, no correlations were observed between trough monocyte or granulocyte TNF receptors and peak plasma concentrations of soluble TNF receptors. Stimulation of human whole blood with endotoxin resulted in reduced expression of both type I and type II TNF receptors on monocytes and granulocytes. Endotoxin induces downmodulation of monocyte and granulocyte TNF surface receptors in humans in vivo, which may represent a mechanism to reduce excessive activity of TNF during systemic infection.