NF-kappaB controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program.

摘要

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.