TGF-BETA AND ENDOTHELIAL-CELLS INHIBIT VCAM-1 EXPRESSION ON HUMAN VASCULAR SMOOTH-MUSCLE CELLS

Vascular smooth muscle cells (VSMCs) are normally devoid of the adhesi on protein vascular cell adhesion molecule-1 (VCAM-1), which has, howe ver, been observed on human VSMCs in atheroma. We now show that cultur ed human saphenous vein VSMCs express small amounts of VCAM-1 and that the cytokine tumor necrosis factor-alpha (TNF-alpha) induces, in a ti me- and dose-dependent fashion, a significant increase in its expressi on. Interleukin (IL)-4, IL-1, and to a lesser extent interferon gamma have similar effects. TNF-alpha-stimulated human VSMCs demonstrate inc reased binding of T lymphocytes that is totally VCAM-1 mediated. The c ytokine transforming growth factor-beta (TGF-beta) at 2.0 ng/mL inhibi ted basal VCAM-1 expression by 84+/-8% and the induction by TNF-alpha by between 56+/-16% and 77+/-15% depending on the dose of TNF. Further more, coculture on opposing sides of a polycarbonate filter of human V SMCs with human umbilical vein endothelial cells also inhibited the in duction of VCAM-1 by 47+/-6%. As active TGF-beta is produced upon the coculture of VSMCs and endothelial cells, we suggest that the close ph ysical proximity of these cells in vivo is responsible for the lack of expression of VCAM-1 on VSMCs and that the interruption of this conta ct in atheroma is an important pathogenic event. As VCAM-1 not only se rves as an adhesion molecule but also as a costimulator of immune cell s, its expression may be crucial in the propagation of vascular lesion s.