MODULATION OF MONOCYTE TYPE-I TRANSFORMING GROWTH-FACTOR-BETA RECEPTORS BY INFLAMMATORY STIMULI

The regulatory mechanisms which control the wide array of cellular responses to transforming growth factor-beta (TGF-beta) are not understood. This report presents evidence that down-regulation of TGF-beta receptors on human monocytes may be one mechanism by which the effects of TGF-beta are regulated. Treatment of monocytes with interferon-gamma (IFN-gamma) and lipopolysaccharide for 18 h reduced monocyte receptor number (approximately 400/cell) in a dose-dependent fashion by 89 and 78%, respectively, as determined by I-125-TGF-beta binding. Incubation with other cytokines (granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor-1, interleukin-1, tumor necrosis factor-alpha) did not alter the amount of TGF-beta bound. The decrease in I-125-TGF-beta binding could not be attributed to competition for receptor sites by secreted TGF-beta. Instead, the decline in binding was due to a loss of type I TGF-beta receptors, the subtype primarily expressed by monocytes, with no decrease in receptor affinity. Lipopolysaccharide-induced receptor loss was rapid (1-4 h), in contrast to the prolonged (12 h) decline induced by IFN-gamma. Loss of receptors was accompanied by a diminished ability of the cells to respond to TGF-beta with an induction of TNF-alpha mRNA. Thus, this monocyte system is the first example of a heterologous agent causing the down-regulation of TGF-beta receptors with a concomitant decline in a TGF-beta-stimulated function.