The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and
metastasis. It has been demonstrated that in human models,
cytokines such as TNF,
IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of
cell adhesion molecules on endothelial cell surfaces. We and others have shown similar
cytokine-induced endothelial adhesiveness for
tumor cells in murine and human models. In contrast to the effect of those modulators,
transforming growth factor-beta (
TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of
TGF-beta action remains unknown. Little is known about the effect of
TGF-beta on
tumor cell-endothelial interaction. In the present study, we demonstrate that
TGF-beta inhibits basal and TNF-enhanced binding of murine P815
mastocytoma cells to murine microvascular endothelium (
MME). The alterations in
MME mediated by
TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine
B16 melanoma cells. The effect of
TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to
MME. The
TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on
protein synthesis because
cycloheximide reverses the
TGF-beta effect.
TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of
G proteins do not abolish
TGF-beta action,
protein kinase C and
protein kinase A activators elicit an effect opposite to that of the factor,
TGF-beta does not increase intracellular cAMP levels, and finally
calcium-mobilizing agents do not mimic, but rather inhibit the effect of
TGF-beta. However,
TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to
MME is completely abolished in the presence of the
protein phosphatase inhibitor
okadaic acid which suggests that
TGF-beta may elicit its effect by stimulating
protein phosphatase activity.