12-O-tetradecanoylphorbol-13-acetate- and tumor necrosis factor α- mediated induction of intercellular adhesion molecule-1 is inhibited by dexamethasone. Functional analysis of the human intercellular adhesion molecule-1 promoter

Transcription regulation of the human intercellular adhesion molecule-1 gene by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), tumor necrosis factor α (TNFα), and the glucocorticoid dexamethasone was studied using transient transfections in 293 cells with intercellular adhesion molecule-1 promoter-luciferase constructs (together with a glucocorticoid receptor expression vector). TPA and TNFα induced promoter activity, which was repressed by dexamethasone. Four TPA-responsive DNA regions were identified, each containing a potential TPA-responsive enhancer sequence: 1) -677/-340 an AP3-like sequence; 2) -290/278 a TPA-response element (TRE); 3) -227/-175 an NFκB-like sequence; 4) -105/-38 an AP2-like sequence. TNFα enhanced transcription only through region 3. The TRE in region 2 appeared to be functionally coupled to a distal TATA box at -313 and differed from the consensus TRE with respect to binding characteristics for members of the AP1 family. The newly identified NFκB enhancer (TGGAAATTCC) is bound by a TNFα- induced nuclear protein and appears to be the key element in rapid transcription induction by TNFα (and TPA), while transactivation of this element is repressed by the ligand-bound glucocorticoid receptor. We propose a negative cross-talk between the NFκB transcription factor and the glucocorticoid receptor.