NF-kappa B activation is required for human endothelial survival during exposure to tumor necrosis factor-alpha but not to interleukin-1 beta or lipopolysaccharide

In the presence of a protein synthesis inhibitor, cyclohexeimide, tumor nec rosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), or lipopoly saccharide (LPS) induces human umbilical vein endothelial cells (HUVECs) to undergo apoptosis, suggesting that constitutive or inducible cytoprotectiv e pathways are required for cell survival. We studied the correlation betwe en 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 domi nant-negative I kappa B alpha (inhibitor of kappa B) mutant blocked NF-kapp a B activation by gel shift assay and blocked induction of vascular cell ad hesion molecule-1 protein by TNF-alpha, IL-1 beta, and LPS, a NF-kappa B-de pendent response. In cells overexpressing the I kappa B alpha mutant, TNF-a lpha 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.