NF-κB activation is required for human endothelial survival during exposure to tumor necrosis factor-α but not to interleukin-1β or lipopolysaccharide

In the presence of a protein synthesis inhibitor, cyclohexeimide, tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), or lipopolysaccharide (LPS) induces human umbilical vein endothelial cells (HUVECs) to undergo apoptosis, suggesting that constitutive or inducible cytoprotective pathways are required for cell survival. We studied the correlation between nuclear factor-kappa B (NF-kappa B) activation and cell death induced by TNF-alpha, IL-1 beta, or LPS. Adenovirus-mediated overexpression of a dominant-negative I kappa B alpha (inhibitor of kappa B) mutant blocked NF-kappa B activation by gel shift assay and blocked induction of vascular cell adhesion molecule-1 protein by TNF-alpha, IL-1 beta, and LPS, a NF-kappa B-dependent response. In cells overexpressing the I kappa B alpha mutant, TNF-alpha induced cell death, whereas IL-1 beta or LPS did not. We conclude that cell survival following TNF-alpha stimulation is NF-kappa B-dependent but that a constitutive or inducible NF-kappa B-independent pathway(s) protects IL-1 beta- or LPS-treated HUVECs from cell death.