A proteasome inhibitor reduces concurrent, sequential, and long-term IL-1 - and TNF- -induced ECAM expression and adhesion

Dagia, Nilesh M., and Douglas J. Goetz. A proteasome inhibitor reduces concurrent, sequential, and long-term IL1 and TNF-induced ECAM expression and adhesion. Am J Physiol Cell Physiol 285: C813–C822, 2003. First published June 4, 2003; 10.1152/ajpcell.00102.2003.—A promising approach for reducing aberrant leukocyte-endothelial adhesion during pathological inflammation is to inhibit endothelial cell adhesion molecule (ECAM) expression at the transcription level. Several compounds have been shown to decrease cytokine-induced upregulation of ECAMs primarily by modulating the activity of transcription factors [e.g., nuclear factorB (NFB)]. The majority of the in vitro studies have focused on the effect of transcription inhibitors on endothelial cells exposed to a single cytokine [primarily tumor necrosis factor(TNF)] for a relatively short period of time (primarily 4–6 h). However, in the in vivo setting, multiple cytokines [e.g., interleukin-1 (IL-1 ) and TNF] may be present for extended periods of time. Thus we studied the effects of a transcription inhibitor, the proteasome inhibitor lactacystin, on ECAM expression and myeloid (HL60) cell adhesion to human umbilical vein endothelial cells (HUVEC) activated by concurrent, sequential, and long-term (24 h) treatment with IL-1 and TNF. We show, for the first time, that lactacystin inhibits 1) 4-h concurrent IL-1 and TNF-induced expression of E-selectin, VCAM-1, ICAM-1, and HL60 cell adhesion to HUVEC; 2) 4-h TNF-induced expression of E-selectin, VCAM-1, and HL60 cell adhesion to HUVEC that have become desensitized to IL-1 activation; 3) 24-h TNF-induced expression of E-selectin and VCAM-1 but not ICAM-1; and 4) 24-h TNF-induced HL60 cell adhesion to HUVEC. Combined, our results demonstrate that a proteasome inhibitor can reduce concurrent, sequential, and long-term IL-1 and TNF-induced ECAM expression and myeloid cell adhesion.