Regulation of vascular cell adhesion molecule-1 expression by IL-4 and TNF-alpha in cultured endothelial cells.
Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and alpha 4 integrins on leukocytes is thought to mediate the selective recruitment of eosinophils and lymphocytes that occurs in allergic diseases. IL-4 is associated with allergic conditions, and it has been shown to selectively increase expression of VCAM-1 on endothelial cells in vivo, suggesting that it could be responsible for VCAM-1 expression in allergic disease. Using a combination of immunofluorescence, flow cytometry, and Northern analysis, we compared the effect of TNF-alpha and IL-4 on VCAM-1 expression. TNF-alpha is also associated with allergic diseases, and it rapidly increases transcription of the VCAM-1 gene. The effect of IL-4 was relatively modest with prolonged kinetics: VCAM-1 was not detected until 72 h after treatment with IL-4. However, when TNF-alpha and IL-4 were combined, there was a synergistic increase in VCAM-1 expression and a dramatic prolongation of the appearance of VCAM-1 on the cell surface. This synergy results from a combination of transcriptional activation by TNF-alpha and the stabilization of resulting transcripts by IL-4. We propose that IL-4 allows subthreshold concentrations of TNF-alpha (concentrations that would not normally activate expression of adhesion molecules on the endothelium) to selectively increase VCAM-1 expression and to prolong its appearance on the surface of cells in allergic disease.
Iademarco
M F
MF
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Barks
J L
JL
Dean
D C
DC
D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification; D002478:Cells, Cultured; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006207:Half-Life; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D007231:Infant, Newborn; D015847:Interleukin-4 / Q000494:pharmacology*; D007700:Kinetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4