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 endo thelial cells and (alpha 4 integrins on leukocytes is thought to media te the selective recruitment of eosinophils and lymphocytes that occur s in allergic diseases. IL-4 is associated with allergic conditions, a nd it has been shown to selectively increase expression of VCAM-1 on e ndothelial cells in vivo, suggesting that it could be responsible for VCAM-1 expression in allergic disease. Using a combination of immunofl uorescence, flow cytometry, and Northern analysis, we compared the eff ect of TNF-alpha and IL-4 on VCAM-1 expression. TNF-alpha is also asso ciated with allergic diseases, and it rapidly increases transcription of the VCAM-1 gene. The effect of IL-4 was relatively modest with prol onged kinetics: VCAM-1 was not detected until 72 h after treatment wit h IL-4. However, when TNF-alpha and IL-4 were combined, there was a sy nergistic increase in VCAM-1 expression and a dramatic prolongation of the appearance of VCAM-1 on the cell surface. This synergy results fr om a combination of transcriptional activation by TNF-alpha and the st abilization of resulting transcripts by IL-4. We propose that IL-4 all ows subthreshold concentrations of TNF-alpha (concentrations that woul d not normally activate expression of adhesion molecules on the endoth elium) to selectively increase VCAM-1 expression and to prolong its ap pearance on the surface of cells in allergic disease.