title: A sustained reduction in IkappaB-beta may contribute to persistent NF-kappaB activation in human endothelial cells.
abstract: The responses of vascular endothelial cells (EC) to tumor necrosis factor-alpha (TNF), interleukin-1alpha (IL-1), and phorbol myristate acetate (PMA) were compared with respect to the kinetics of (i) NF-kappaB activation, (ii) IkappaB-alpha and IkappaB-beta degradation, and (iii) NF-kappaB-dependent cell surface molecule expression. TNF rapidly (</=20 min) and persistently (>20 h) activates NF-kappaB; IL-1 rapidly activates NF-kappaB, but activity declines by 3 h and further by 20 h; PMA slowly and transiently activates NF-kappaB. Untreated EC contain the inhibitory proteins IkappaB-alpha and IkappaB-beta. The onset of NF-kappaB activation correlates with degradation of IkappaB-alpha, but IkappaB-alpha reappears by 4 h without resequestration of NF-kappaB. TNF causes a rapid but partial (50%) reduction in IkappaB-beta, which does not recover by 22 h; IL-1 and PMA cause slower and less sustained reductions in IkappaB-beta. All three agonists induce de novo expression of E-selectin (CD62E) and vascular cell adhesion molecule-1 (CD106) and increase expression of intercellular adhesion molecule-1 (CD54) at 4 h. TNF induces sustained increases in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and increases human leukocyte antigen class I molecules at 24 h. We conclude that TNF causes persistent activation of NF-kappaB in human EC and that this may result from sustained reductions in IkappaB-beta levels.
authors.affiliation: Department of Pathology, Boyer Center for Molecular Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Johnson
authors.forename: I
authors.initials: I
authors.lastname: Douglas
authors.forename: A
authors.initials: A
authors.lastname: Jahnke
authors.forename: S
authors.initials: S
authors.lastname: Ghosh
authors.forename: J S
authors.initials: JS
authors.lastname: Pober
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000096:biosynthesis; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016384:Consensus Sequence; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; D013755:Tetradecanoylphorbol Acetate