COORDINATE AND COOPERATIVE ROLES FOR NF-AT AND AP-1 IN THE REGULATION OF THE MURINE IL-4 GENE

The transcription factor NF-AT plays an essential role in the inducible transcription of several cytokine genes during T cell activation. The distal NF-AT site of the murine IL-2 promoter binds both NF-AT and AP-1 proteins, and thus represents a composite regulatory site that integrates Ca2+- and PKC-dependent signaling pathways in T cell activation. However, the individual contributions of the NF-AT and AP-1 components to promoter activity via this composite site have not been resolved, owing to the absence of a clearly defined AP-1 binding site, which, when mutated abolishes AP-1 binding. We describe here an apparently analogous NF-AT/AP-1 composite site in the murine IL-4 promoter, which can be mutated to selectively block the recruitment of each component. We show that the cooperative and coordinate involvement of both NF-AT and AP-1 is necessary for full activity of the NF-AT/AP-1 composite site, and, ultimately, the entire IL-4 promoter.