THE PROTEASOME PATHWAY IS REQUIRED FOR CYTOKINE-INDUCED ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULE EXPRESSION

Multiple cell adhesion protei ns are up-regulated in vascular endothel ial cells in response to TNF alpha and other inflammatory cytokines. T his increase in cell adhesion gene expression is thought to require th e transcription factor NF-KB. Here, we show that peptide aldehyde inhi bitors of the proteasome, a multicatalytic protease recently shown to be required for the activation of NF-kappa B, block TNF alpha inductio n of the leukocyte adhesion molecules E-selectin, VCAM-1, and ICAM-1. Striking functional consequences of this inhibition were observed in a nalyses of leukocyte-endothelial interactions under defined flow condi tions. Lymphocyte attachment to TNF alpha-treated endothelial monolaye rs was totally blocked, while neutrophil attachment was partially redu ced but transmigration was essentially prevented.