REGULATION OF VASCULAR CELL-ADHESION MOLECULE-1 AND INTERCELLULAR-ADHESION MOLECULE-1 IN HUMAN VASCULAR SMOOTH-MUSCLE CELLS

Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion mol ecule-1 (ICAM-1), and E-selectin are inducible proteins involved in ce ll-cell adhesion. Immunohistochemical studies have indicated that huma n atherosclerotic plaques contain smooth muscle cells (SMCs) that expr ess ICAM-1 and VCAM-1. Recently, we demonstrated that SMCs in culture express a functionally active cytokine-inducible ICAM-1. SMCs and mono nuclear cells participate in the local accumulation of cytokines and r elated growth factors in atherosclerotic lesions. Therefore, we determ ined the effects of different cytokines and growth factors on mRNA con tent and cell surface expression of VCAM-1, ICAM-1, and E-selectin in cultured human aortic SMCs by Northern blotting, quantitative polymera se chain reaction amplification, and immunofluorescence flow cytometry . Under basal conditions of cultivation, both VCAM-1 mRNA and membrane expression of VCAM-1 were low and were induced very little by interle ukin-1 beta (100 U/mL). Platelet-derived growth factor or transforming growth factor-beta decreased VCAM-1 mRNA basal expression. Treatment of SMCs with tumor necrosis factor-alpha (TNF-alpha) led to an increas e in both VCAM-1 mRNA and cell surface expression for VCAM-1 in a dose - and time-dependent manner. Interferon-gamma induced a weak increase in VCAM-1 mRNA expression, with no synergistic effect on the stimulati on by TNF-alpha. Various differences were noted between the expression of ICAM-1 and VCAM-1 genes, because interleukin-1 beta induced substa ntial amounts of ICAM-1 but not VCAM-1. The addition of interferon-gam ma delays the time at which peak expression of ICAM-1 in response to T NF-alpha stimulation occurs. Under our conditions, we did not detect a ny expression of E-selectin by SMCs. These results suggest that cytoki nes regulate VCAM-1 and ICAM-1 expression on arterial SMCs and could p lay an important role in the pathophysiology of inflammatory and immun e processes in atherosclerosis.