NF-kappaB controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program.
Activation of the transcription factor NF-kappaB is critical for the tumor necrosis factor-alpha (TNF-alpha)-induced inflammatory response. Here we report the complete gene expression profile from activated microvascular endothelial cells emphasizing the direct contribution of the NF-kappaB pathway. Human microvascular endothelial cell line-1 (HMEC-1) cells were modified to express dominant interfering mutants of the IKK/NF-kappaB signaling module and expression profiles were determined. Our results provide compelling evidence for the virtually absolute dependence of TNF-alpha-regulated genes on NF-kappaB. A constitutively active IKK2 was sufficient for maximal induction of most target genes, whereas a transdominant IkappaBalpha suppressed gene expression. Several genes with a critical role in atherogenesis were identified. The endothelial lipase (EL) gene, a key enzyme involved in lipoprotein metabolism, was investigated more in detail. Binding sites interacting with NF-kappaB in vitro and in vivo were identified and co-transfection experiments demonstrated the direct regulation of the EL promoter by NF-kappaB. We conclude that targeting the IKK/NF-kappaB pathway or specific genes downstream may be effective for the control or prevention of chronic inflammatory diseases such as atherosclerosis.
Kempe
Sybille
S
Department of Physiological Chemistry, University of Ulm Albert Einstein Allee 11, Ulm 89081, Germany.
Kestler
Hans
H
Lasar
Andrea
A
Wirth
Thomas
T
D001161:Arteriosclerosis / Q000201:enzymology / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase; D018836:Inflammation Mediators / Q000494:pharmacology; D008049:Lipase / Q000235:genetics*; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051179:Plakins; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C491674:PPL protein, human; D051179:Plakins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C410382:LIPG protein, human; D008049:Lipase