A sustained reduction in I kappa B-beta may contribute to persistent NF-kappa B activation in human endothelial cells

The responses of vascular endothelial cells (EC) to tumor necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1), and phorbol myristate acetate (PMA) were compared with respect to the kinetics of (i) NF-kappa B activation, (ii) I kappa B-alpha and I kappa B-beta degradation, and (iii) NF-kappa B-dependent cell surface molecule expression, TNF rapidly (less than or equal to 20 min) and persistently (>20 h) activates NF-kappa B; IL-1 rapidly activates NF-kappa B, but activity declines by 3 h and further by 20 h; PMA slowly and transiently activates NF-kappa B, Untreated EC contain the inhibitory proteins I kappa B-alpha and I kappa B-beta, The onset of NF-kappa B activation correlates with degradation of I kappa B-alpha, but I kappa B-alpha reappears by 4 h without resequestration of NF-kappa B. TNF causes a rapid but partial (50%) reduction in I kappa B-beta, which does not recover by 22 h; IL-1 and PMA cause slower and less sustained reductions in I kappa B-beta. All three agonists induce de novo expression of E-selectin (CD62E) and vascular cell adhesion molecule-1 (CD106) and increase expression of intercellular adhesion molecule-1 (CD54) at 4 h. TNF induces sustained increases in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and increases human leukocyte antigen class I molecules at 24 h, We conclude that TNF causes persistent activation of NF-kappa B in human EC and that this may result from sustained reductions in I kappa B-beta levels.