title: NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation.
abstract: Structural analysis of the promoters of several endothelial genes induced at sites of inflammatory or immune responses reveals binding sites for the transcription factor nuclear factor kappa B (NF-kappa B). Endothelial cells express transcripts encoding the p50/p105 and p65 components of NF-kappa B and the rel-related proto-oncogene c-rel; steady state levels of these transcripts are transiently increased by tumor necrosis factor alpha (TNF-alpha). Western blotting revealed that stimulation of endothelial cells with TNF-alpha resulted in nuclear accumulation of the p50 and p65 components of NF-kappa B. Ultraviolet crosslinking and immunoprecipitation demonstrated binding of the p50 and p65 components of NF-kappa B to the E-selectin kappa B site. Endothelial cells express an inhibitor of NF-kappa B activation, I kappa B-alpha (MAD-3). Protein levels of this inhibitor fall rapidly after TNF-alpha stimulation. In parallel, p50 and p65 accumulate in the nucleus and RNA transcript levels for I kappa B-alpha are dramatically upregulated. Recombinant p65 stimulates expression of E-selectin promoter-reporter constructs. I kappa B-alpha inhibits p65 or TNF-alpha-stimulated E-selectin promoter-reporter gene expression in transfected endothelial cells. The NF-kappa B and I kappa B-alpha system may be an inducible regulatory mechanism in endothelial activation.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: M A
authors.initials: MA
authors.lastname: Read
authors.forename: M Z
authors.initials: MZ
authors.lastname: Whitley
authors.forename: A J
authors.initials: AJ
authors.lastname: Williams
authors.forename: T
authors.initials: T
authors.lastname: Collins
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D004268:DNA-Binding Proteins; D019040:E-Selectin; D020672:I-kappa B Proteins; C000715470:MAS1 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA