REGULATORY ELEMENTS AND TRANSCRIPTION FACTORS CONTROLLING BASAL AND CYTOKINE-INDUCED EXPRESSION OF THE GENE ENCODING INTERCELLULAR-ADHESIONMOLECULE-1

The gene encoding intercellular adhesion molecule 1 (ICAM-1) is transc riptionally induced in response to inflammatory and immunomodulatory c ytokines. To investigate the mechanisms controlling ICAM-1 gene expres sion, we have identified regulatory DNA sequences responsible for main taining basal and mediating induced transcription in response to tumor necrosis factor cu (TNF-alpha) and interferon gamma (IFN-gamma). Regu latory elements centered 115, 60, and 40 bp upstream from the ICAM-1 t ranscription start site were implicated in cytokine-independent gene e xpression. Regulatory elements dedicated to TNF-alpha and IFN-gamma we re identified 190 and 90 bp, respectively, upstream from the ICAM-1 tr anscription start site. A combination of mutagenesis and DNA binding a ssays revealed that the TNF-alpha response element is composite, consi sting of binding sites for both C/EBP and NF-kappa B. The IFN-gamma re sponse element behaved as a simple regulatory element that selectively binds to an IFN-gamma-inducible activity composed, at least in part, of p91. These observations provide a framework for understanding how e xtracellular signals dynamically regulate the adhesive properties of m ammalian cells.