THE ROLE OF NF-Y AND IRF-2 IN THE REGULATION OF HUMAN IL-4 GENE-EXPRESSION

Activity of the IL-4 promoter was shown to be regulated by multiple ci s-acting elements. In this study, two additional regulatory elements, a CCAAT element and a 15-nucleotide element homologous to the IFN- and virus-stimulation response element (ISRE), were identified in the hum an promoter region at -195 to -172. The ISRE-homologous sequence was s hown to interact with two nuclear proteins, IRF-2, a transcriptional r epressor of the IFN genes, and an NF-1-like factor. Mutations of the I SRE site increased overall IL-4 promoter activity twofold, suggesting a possible negative role of IRF-2 in the regulation of IL-4 transcript ion. The CCAAT element was found to interact with NF-Y, a nuclear fact or essential for expression of MHC class II genes. Mutations of the CC AAT element at -195 to -172 resulted in a substantial decrease of IL-4 promoter activity. Furthermore, NF-Y was also found to bind to the pr eviously described NF-AT(p) binding site of the IL-4 promoter (-79 to -62, originally described as ''P element''), and the previously descri bed P-binding complex NF-P was shown to contain NF-Y. These findings s uggest that NF-Y may play an important role in the regulation of IL-4 gene expression.