Activation of NF-kappa B via the Ikappa B kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells

The Journal of Biological Chemistry
Andrea DenkThomas Wirth

Abstract

Activation of the transcription factor NF-kappaB is necessary for full expression of tumor necrosis factor alpha (TNF-alpha)-inducible endothelial chemokines and adhesion molecules. However, a detailed analysis regarding contribution of the different NF-kappaB upstream components to endothelial activation has not been performed yet. We employed a retroviral infection approach to stably express transdominant (TD) mutants of IkappaBalpha, IkappaBbeta, or IkappaBepsilon and dominant negative (dn) versions of IkappaB kinases (IKK) 1 or 2 as well as a constitutively active version of IKK2 in human endothelial cells. TD IkappaBalpha, IkappaBbeta, and IkappaBepsilon were not degraded upon TNF-alpha exposure, and each prevented NF-kappaB activation. These TD IkappaB mutants almost completely inhibited the induction of monocyte chemoattractant protein-1, interleukin-8, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression by TNF-alpha, whereas interferon-gamma-mediated up-regulation of intercellular adhesion molecule-1 and HLA-DR was not affected. Expression of dn IKK2 completely blocked TNF-alpha-induced up-regulation, whereas dn IKK1 showed a partial inhibition of expression of these molecules...Continue Reading

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