Published online 21 September 2005
Article |
NF-
B controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program
Department of Physiological Chemistry, University of Ulm Albert Einstein Allee 11, Ulm 89081, Germany 1Department of Neuroinformatics and Internal Medicine I, University of Ulm Albert Einstein Allee 11, Ulm 89081, Germany
*To whom correspondence should be addressed. Tel: +49 0 731 502 3270; Fax: +49 0 731 502 2892; Email: thomas.wirth{at}medizin.uni-ulm.de
Received June 2, 2005. Revised August 30, 2005. Accepted August 30, 2005.
Activation of the transcription factor NF-
B is critical for the tumor necrosis factor-
(TNF-)-induced inflammatory response. Here we report the complete gene expression profile from activated microvascular endothelial cells emphasizing the direct contribution of the NF-B pathway. Human microvascular endothelial cell line-1 (HMEC-1) cells were modified to express dominant interfering mutants of the IKK/NF-B signaling module and expression profiles were determined. Our results provide compelling evidence for the virtually absolute dependence of TNF--regulated genes on NF-B. A constitutively active IKK2 was sufficient for maximal induction of most target genes, whereas a transdominant IB 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-B in vitro and in vivo were identified and co-transfection experiments demonstrated the direct regulation of the EL promoter by NF-B. We conclude that targeting the IKK/NF-B pathway or specific genes downstream may be effective for the control or prevention of chronic inflammatory diseases such as atherosclerosis.
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