SYNERGISTIC ACTIVATION OF INTERCELLULAR-ADHESION MOLECULE-1 (ICAM-1) BY TNF-ALPHA AND IFN-GAMMA IS MEDIATED BY P65 P50 AND P65/1C-REL AND INTERFERON-RESPONSIVE FACTOR STAT1-ALPHA (P91) THAT CAN BE ACTIVATED BYBOTH IFN-GAMMA AND IFN-ALPHA/

Human ICAM-1 expression is up-regulated by IFN-gamma and TNF-alpha, an d synergistically increased by a combination of both. Transient expres sion of ICAM-1/luciferase constructs led to definition of the regulato ry regions mediating the cytokine response and showed that both are ne cessary for synergism. Immunochemical electromobility shift assays ide ntified the TNF-alpha-dependent complexes that bound to the NF-kappa B like sequence at -187 as p65/p50 and p65/c-Rel. The interferon respon sive region at -75 was bound by a Statl alpha (p91) containing complex that was activated by both IFN-gamma and IFN-alpha. Although both reg ions were required for synergism, no additional or enhanced binding co mplexes were observed.