Synergistic activation of intercellular adhesion molecule 1 (ICAM-1) by TNF-alpha and IFN-gamma is mediated by p65/p50 and p65/c-Rel and interferon-responsive factor Stat1 alpha (p91) that can be activated by both IFN-gamma and IFN-alpha.

Human ICAM-1 expression is up-regulated by IFN-gamma and TNF-alpha and synergistically increased by a combination of both. Transient expression of ICAM-1/luciferase constructs led to definition of the regulatory regions mediating the cytokine response and showed that both are necessary for synergism. Immunochemical electromobility shift assays identified 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 responsive region at -75 was bound by a Stat1 alpha (p91) containing complex that was activated by both IFN-gamma and IFN-alpha. Although both regions were required for synergism, no additional or enhanced binding complexes were observed.