NF-κB controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program
Activation of the transcription factor NF-κB is critical for the tumor necrosis factor-α (TNF-α)-induced inflammatory response. Here we report the complete gene expression profile from activated microvascular endothelial cells emphasizing the direct contribution of the NF-κB pathway. Human microvasc...
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Published in | Nucleic acids research Vol. 33; no. 16; pp. 5308 - 5319 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Oxford University Press
01.01.2005
Oxford Publishing Limited (England) |
Online Access | Get full text |
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Summary: | Activation of the transcription factor NF-κB is critical for the tumor necrosis factor-α (TNF-α)-induced inflammatory response. Here we report the complete gene expression profile from activated microvascular endothelial cells emphasizing the direct contribution of the NF-κB pathway. Human microvascular endothelial cell line-1 (HMEC-1) cells were modified to express dominant interfering mutants of the IKK/NF-κB signaling module and expression profiles were determined. Our results provide compelling evidence for the virtually absolute dependence of TNF-α-regulated genes on NF-κB. A constitutively active IKK2 was sufficient for maximal induction of most target genes, whereas a transdominant IκBα 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-κB in vitro and in vivo were identified and co-transfection experiments demonstrated the direct regulation of the EL promoter by NF-κB. We conclude that targeting the IKK/NF-κB pathway or specific genes downstream may be effective for the control or prevention of chronic inflammatory diseases such as atherosclerosis. |
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Bibliography: | istex:90802FA5E4C4C7A63106612EC1BB5D749540D773 local:gki836 ark:/67375/HXZ-9PH8FL8B-R To whom correspondence should be addressed. Tel: +49 0 731 502 3270; Fax: +49 0 731 502 2892; Email: thomas.wirth@medizin.uni-ulm.de ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0305-1048 1362-4962 |
DOI: | 10.1093/nar/gki836 |