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 endothelium and vascular smooth muscle in atherosclerosis, where it is thought to recruit alpha4 integrin-positive leukocytes, which play a role in disease progression. In this study, we show an increase of VCAM-1 expression on vascular smooth muscle cells (VSMC) results in increased adhesion of alpha4 integrin-positive lymphocytes. Additionally, we examine the regulation of VCAM-1 expression by cytokines in cultured VSMC. Previously in endothelial cells, we have demonstrated that TNF-alpha increases transcription of the VCAM-1 gene, whereas IL-4 acts to increase VCAM-1 mRNA stability. The combination of a cytokine that increases transcription with a cytokine that stabilizes mRNA results in a synergistic 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 cytokine activation differed. In contrast to endothelial cells, IL-4 stimulated VCAM-1 gene transcription in the VSMC, but there was little effect of TNF-alpha alone. Additionally, the synergy between TNF-alpha and IL-4 appears to result, at least in part, from a cooperative transcriptional mechanism.
Barks
J L
JL
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
McQuillan
J J
JJ
Iademarco
M F
MF
D002478:Cells, Cultured; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4