Transforming growth factor-beta (TGF-beta), a pleiotropic cytokine that is elaborated in the active form upon co-culture of endothelial cells and pericytes or smooth muscle cells, has been shown to decrease the adhesiveness of endothelial cells for neutrophils, lymphocytes, and tumor cells. The mechanism whereby TGF-beta inhibits the adhesiveness of human endothelial cells was investigated. TGF-beta inhibited the basal E-selectin (formerly ELAM-1) expression by 55 +/- 7% and TNF-stimulated expression by 57 +/- 4%. Similar decreases of IL-1-stimulated expression were also seen. Peak inhibition was seen at TGF-beta doses between 0.2 and 2 ng/ml. Both TGF-beta 1 and -beta 2 were functional. The effectiveness of TGF-beta in inhibiting E-selectin expression was dependent on cell density and incubation time. TGF-beta also inhibited E-selectin mRNA levels in endothelial cells. TGF-beta had no effect on the expression of VCAM-1 and ICAM-1, but was additive with IL-4 in inhibiting the expression of E-selectin. The expression of E-selectin has been shown to mediate several aspects of the inflammatory response involving neutrophils and memory T lymphocytes. Perivascular TGF-beta appears to act as an inhibitor of the expression of the endothelium-specific selectin, E-selectin, and therefore of inflammatory responses involving neutrophils and (a subset of) lymphocytes.