The Role of RELA (p65) in Regulation of NF-kappaB Homeostasis: Implications for Atherosclerosis

The NF-κB/Rel family of transcription factors and IκB inhibitors play a key role in regulation of gene expression in inflammation and immunity. Previous studies from our laboratory suggested that steady-state levels of p65 and other NF-κB components in the normal mouse aorta determine the magnitude of NF-κB target gene expression in response to pro-inflammatory stimuli, however, the mechanism(s) by which steady-state levels of NF-κB components are set is not clear. This study aims at elucidating the mechanisms behind NF-κB homeostasis and how that affects atherosclerosis susceptibility. In HeLa cells and HUVEC, siRNA silencing of p65 correlated with reduced steady-state expression of a subset of NF-κB/Rel and IκB genes at the transcriptional and post-transcriptional levels, respectively, in addition to reducing TNFα-induced NF-κB/Rel and IκB gene expression. This correlation was also observed in atherosclerosis-susceptible mouse aortic endothelium suggesting the role of p65 in modulating NF-κB homeostasis and affecting atherosclerosis susceptibility.MAS