Differential effects of lactacystin on IL-1 beta and TNF-alpha induced adhesion molecule expression and myeloid cell adhesion to endothelial cells

Abstract

Proteasome inhibitors (e.g. lactacystin) have been shown to decrease cytokine-induced up-regulation of endothelial cell adhesion molecules and consequent leukocyte adhesion. The majority of these studies have focused on the effects of proteasome inhibitors on endothelial cells exposed to a single cytokine (TNF alpha) for 4 hrs. However, in the in vivo setting, multiple cytokines (e.g. IL-1 beta and TNF alpha) may be present and their levels may be increased for extended periods off time. In addition, the effects of IL-1 beta (IL-1) and TNF alpha (TNF) on endothelial cells are not identical. Thus, we studied the effect of lactacystin on IL-1 and TNF induced adhesion molecule expression and myeloid cell (HL-60 cells) adhesion to human umbilical vein endothelial cells (HUVEC). We found that (a) lactacystin inhibits 4 hr. IL-1 or TNF induced expression of E-selectin, ICAM-1, VCAM-1 and HL-60 cell adhesion to HUVEC, (b) lactacystin differentially inhibits transient adhesive contacts of HL-60 cells to 4 hr. IL-1 and TNF activated HUVEC, (c) lactacystin inhibits 4 hr. TNF induced expression of VCAM-1, E-selectin and HL-60 cell adhesion to IL-1 sefractory HUVEC and (d) lactacystin inhibits HL-60 cell adhesion to 24 hr. TNF activated HUVEC.