IL-1-BETA-INDUCED MONOCYTE CHEMOATTRACTANT PROTEIN-1 GENE-EXPRESSION IN ENDOTHELIAL-CELLS IS BLOCKED BY PROTEASOME INHIBITORS

Human monocyte chemoattractant protein-1 (MCP-1) is expressed by a var iety of cell types in response to various stimuli. MCP-1 expressed by the endothelium plays an important role in cell migration and activati on. MCP-I is a major chemoattractant for monocytes, T lymphocytes, and basophils. In the present study, we present evidence that the proteas ome complex is involved in mediating the interleukin (IL)-1 beta induc tion of MCP-1 in endothelial cells. We present evidence that a proteas ome inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal (norLeu), and th e protease inhibitor tosyl-Phe-chloromethylketone (TPCK) block IL-1 be ta induction of MCP-1 protein expression. norLeu and TPCK also blocked IL-1 beta-induced MCP-1 promoter-driven reporter gene expression as w ell as nuclear factor (NF)-kappa B-mediated reporter gene expression. The effects of norLeu were due to its inhibition of the proteasome rat her than calpain, because other calpain inhibitors had no effect on MC P-1 expression. In contrast to TPCK, which blocked NF-KB translocation to the nucleus, norLeu had no effect on NF-kappa B nuclear translocat ion or IL-1 beta-induced phosphorylation of p65. This study demonstrat es that the proteasome pathway is involved in IL-1 beta-induced MCP-1 gene expression in human endothelial cells.