TNF-ALPHA AND IL-4 SYNERGISTICALLY INCREASE VASCULAR CELL-ADHESION MOLECULE-1 EXPRESSION IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS

Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the endothe lium and vascular smooth muscle in atherosclerosis, where it is though t to recruit alpha(4) integrin-positive leukocytes, which play a role in disease progression. In this study, we show an increase of VCAM-1 e xpression on vascular smooth muscle cells (VSMC) results in increased adhesion of alpha(4) integrin-positive lymphocytes. Additionally, we e xamine the regulation of VCAM-1 expression by cytokines in cultured VS MC, Previously in endothelial cells, we have demonstrated that TNF-alp ha increases transcription of the VCAM-1 gene, whereas IL-4 acts to in crease VCAM-1 mRNA stability. The combination of a cytokine that incre ases transcription with a cytokine that stabilizes mRNA results in a s ynergistic increase in VCAM-1 expression, In this study, we show that the combination of TNF-alpha with IL-4 also resulted in a synergistic increase in VCAM-1 expression on VSMC; however, the mechanism of cytok ine activation differed, in contrast to endothelial; cells, IL-4 stimu lated VCAM-1 gene transcription in the VSMC, but there was little effe ct of TNF-cu alone. Additionally, the synergy between TNF-alpha and IL -4 appears to result, at least in part, from a cooperative transcripti onal mechanism.