TRANSCRIPTIONAL REGULATION OF ENDOTHELIAL-CELL ADHESION MOLECULES - NF-KAPPA-B AND CYTOKINE-INDUCIBLE ENHANCERS

Transcription of endothelial-leukocyte adhesion molecule-1 (E-selectin or ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercell ular adhesion molecule-1 (ICAM-1) is induced by the inflammatory cytok ines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (T NF alpha). The positive regulatory domains required for maximal levels of cytokine induction have been defined in the promoters of all three genes, DNA binding studies reveal a requirement for nuclear factor-ka ppa B (NF-kappa B) and a small group of other transcriptional activato rs, The organization of the cytokine-inducible element in the E-select in promoter is remarkably similar to that of the virus-inducible promo ter of the human interferon-beta gene in that both promoters require N F-kappa B, activating transcription factor-2 (ATF-2), and high mobilit y group protein I(Y) for induction, Based on this structural similarit y, a model has been proposed for the cytokine-induced E-selectin enhan cer that is similar to the stereospecific complex proposed for the int erferon-beta gene promoter. In these models, multiple DNA bending prot eins facilitate the assembly of higher order complexes of transcriptio nal activators that interact as a unit with the basal transcriptional machinery, The assembly of unique enhancer complexes from similar sets of transcriptional factors may provide the specificity required to re gulate complex patterns of gene expression and correlate with the dist inct patterns of expression of the leukocyte adhesion molecules.