POSTINDUCTION TRANSCRIPTIONAL REPRESSION OF E-SELECTIN AND VASCULAR CELL-ADHESION MOLECULE-1

TNF-alpha induction of the E-selectin and vascular cell adhesion molec ule-1 (VCAM-1) genes leads to transient accumulation of high levels of mRNA in endothelial cells, The increase in these mRNAs after inductio n is due to an increase in the rate of gene transcription, which is ma intained for several hours in the continuous presence of cytokine, Cyt okine-induced transcriptional activation of these genes requires the t ranscription factor, nuclear factor-kappa B, Following removal of TNF- alpha, there is rapid postinduction transcriptional repression common to both of these genes, The repression is protein synthesis dependent and correlates with protein synthesis-dependent loss of both the p50 a nd p65 subunits of nuclear factor-kappa B from the nucleus, I kappa B alpha is capable of specifically displacing endothelial-derived hetero dimeric p50/p65 from the E-selectin and VCAM-1 kappa B elements, while having no effect on binding of p50 homodimer, In the presence of agen ts that block proteasomal degradation of I kappa B alpha, endogenous I kappa K alpha can be visualized in the nucleus of both resting and TN F-alpha-activated endothelial cells, Endogenous I kappa B alpha is rea dily detected in the nucleus of HeLa cells, and its nuclear localizati on is increased following removal of TNF-alpha. Repression of E-select in and VCAM-1 transcription following cytokine removal requires the lo ss of nuclear p50 and p65, and involves I kappa B alpha. This postindu ction transcription repression mechanism may be one component of a pro gram that prevents inappropriate and prolonged expression of adhesion molecules.