Foxp3 induces IL-4 gene silencing by affecting nuclear translocation of NF kappa B and chromatin structure

Abstract

The forkhead family protein Foxp3 is a unique marker of regulatory T cells and plays a crucial role in the development and function of those cells. Ectopic expression of Foxp3 abolishes the expression of many cytokines in uncommitted cells but there is little information about whether it causes gene silencing in differentiated cells. In this study, we showed that ectopic expression of Foxp3 in primary T helper 2 cells abolished IL-4 gene expression. Foxp3 inhibited nuclear translocation of NF kappa B by increasing the stability of the NF kappa B inhibitor I kappa B alpha, which in turn reduced in vivo binding of NF kappa B to the IL-4 promoter region. Moreover, Foxp3 over-expression induced inactive chromatin structure by decreasing in vivo binding levels of acetylated histone 3 while increasing methylated histone 3 at lysine 9 in the IL-4 genomic locus. Our results suggest that Foxp3 could induce gene silencing by inhibiting NF kappa B activity and by causing its target loci to adopt an inactive chromatin configuration. (C) 2008 Elsevier Ltd. All rights reserved.