Multiple cell adhesion proteinsare up-regulated in vascular endothelial cells in response to TNFa and other inflammatory cytokines. This increase in cell adhesion gene expression is thought to require the transcription factor NF-KS. Here, we show that peptide aldehyde inhibitors of the proteasome, a multicatalytic protease recently shown to be required for the activation of NF-KB, block TNFa induction of the leukocyte adhesion molecules E-selectin, VCAM-1, and ICAM-1. Striking functional consequences of this inhibition were observed in analyses of leukocyte-endothelial interactions under defined flow conditions. Lymphocyte attachment to TNFa-treated endothelial monolayer’s was totally blocked, while neutrophil attachment was partially reduced but transmigration was essentially prevented.