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Effect of selective proteasome inhibitors on TNF-induced activation of primary and transformed endothelial cells
Authors:Kalogeris, Theodore J.   Laroux, F. Stephen   Cockrell, Adam   Ichikawa, Hiroshi   Okayama, Naotsuka   Phifer, Travis J.   Alexander, J. Steven   Grisham, Matthew B.
Abstract:The objective ofthis study was to assess the effects of two structurally distinct yetselective proteasome inhibitors (PS-341 and lactacystin) on leukocyteadhesion, endothelial cell adhesion molecule (ECAM) expression, andnuclear factor-kappa B (NF-kappa B) activation in tumor necrosisfactor (TNF)-alpha -stimulated human umbilical vein endothelial cells(HUVEC) and the transformed, HUVEC-derived, ECV cell line. We foundthat TNF (10 ng/ml) significantly enhanced U-937 and polymorphonuclearneutrophil (PMN) adhesion to HUVEC but not to ECV; TNF alsosignificantly enhanced surface expression of vascular cell adhesionmolecule 1 and E-selectin (in HUVEC only), as well as intercellularadhesion molecule 1 (ICAM-1; in HUVEC and ECV). Pretreatment of HUVECwith lactacystin completely blocked TNF-stimulated PMN adhesion,partially blocked U-937 adhesion, and completely blocked TNF-stimulatedECAM expression. Lactacystin attenuated TNF-stimulated ICAM-1expression in ECV. Pretreatment of HUVEC with PS-341 partially blockedTNF-stimulated leukocyte adhesion and ECAM expression. These effects oflactacystin and PS-341 were associated with inhibitory effects onTNF-stimulated NF-kappa B activation in both HUVEC and ECV. Our resultsdemonstrate the importance of the 26S proteasome in TNF-inducedactivation of NF-kappa B, ECAM expression, and leukocyte-endothelialadhesive interactions in vitro.
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