Histone deacetylation inhibits IL4 gene expression in T cells

Background: Dysregulated expression of IL-4 has been linked with allergic diseases. IL-4 expression is controlled at the level of gene transcription by the coordinated action of multiple factors that bind regulatory promoter elements. In addition, alterations in chromatin structure are thought to play a role in regulating the expression of cytokines in the T_H2 gene cluster, although the biochemical basis for these alterations in human T cells is not well understood. Objective: We sought to define the role of histone acetylation in the regulation of IL4 gene expression in human T cells. Methods: IL-4 protein production was measured by means of ELISA. IL-4 promoter activity was measured with luciferasebased reporter constructs transiently transfected into Jurkat T cells. The acetylation status of histones associated with the IL4 gene was analyzed with chromatin immunoprecipitation assays. Results: IL-4 production from activated peripheral blood T cells was enhanced by the histone deacetylase inhibitor trichostatin A. Overexpression of the type 1 histone deacetylases 1, 2, and 3 inhibited transcription driven by the IL-4 promoter in Jurkat T cells, whereas cotransfection of the histone acetyltransferase CREB-binding protein potentiated IL-4 promoter activity. Using chromatin immunoprecipitation assays, we show that nucleosomes in the proximal IL-4 promoter are acetylated on T-cell activation. Conclusion: Our results demonstrate that the acetylation state of histones associated with the IL-4 promoter is a key regulator of IL4 gene expression.