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 adhesion protein vascular cell adhesion molecule-1 (VCAM-1), which has, however, been observed on human VSMCs in atheroma. We now show that cultured human saphenous vein VSMCs express small amounts of VCAM-1 and that the cytokine tumor necrosis factor-alpha (TNF-alpha) induces, in a time- and dose-dependent fashion, a significant increase in its expression. Interleukin (IL)-4, IL-1, and to a lesser extent interferon gamma have similar effects. TNF-alpha-stimulated human VSMCs demonstrate increased binding of T lymphocytes that is totally VCAM-1 mediated. The cytokine transforming growth factor-beta (TGF-beta) at 2.0 ng/mL inhibited 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. Furthermore, coculture on opposing sides of a polycarbonate filter of human VSMCs with human umbilical vein endothelial cells also inhibited the induction 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 physical proximity of these cells in vivo is responsible for the lack of expression of VCAM-1 on VSMCs and that the interruption of this contact in atheroma is an important pathogenic event. As VCAM-1 not only serves as an adhesion molecule but also as a costimulator of immune cells, its expression may be crucial in the propagation of vascular lesions.
Gamble
J R
JR
Hanson Centre for Cancer Research, IMVS, Adelaide, South Australia.
Bradley
S
S
Noack
L
L
Vadas
M A
MA
D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D012501:Saphenous Vein; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4; D007371:Interferon-gamma