LEF-1 Negatively Controls Interleukin-4 Expression through a Proximal Promoter Regulatory Element

• Published in: The Journal of biological chemistry 2008-08, Vol.283 (33), p.22490-22497
• Main Authors: Hebenstreit, Daniel, Giaisi, Marco, Treiber, Monika K., Zhang, Xiao-Bin, Mi, Huai-Feng, Horejs-Hoeck, Jutta, Andersen, Kristian G., Krammer, Peter H., Duschl, Albert, Li-Weber, Min
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - physiology; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation; Humans; Interleukin-4 - genetics; Interleukin-4 - metabolism; Leukemia, T-Cell; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; Mice; Promoter Regions, Genetic; Regulatory Sequences, Ribonucleic Acid - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804096200

Lymphoid enhancer-binding factor 1 (LEF-1) and T cell factor (TCF-1) are downstream effectors of the Wnt signaling pathway and are involved in the regulation of T cell development in the thymus. LEF-1 and TCF-1 are also expressed in mature peripheral primary T cells, but their expression is down-regulated following T cell activation. Although the decisive roles of LEF-1 and TCF-1 in the early stages of T cell development are well documented, the functions of these factors in mature peripheral T cells are largely unknown. Recently, LEF-1 was shown to suppress Th2 cytokines interleukin-4 (IL-4), −5, and −13 expression from the developing Th2 cells that overexpress LEF-1 through retrovirus gene transduction. In this study, we further investigated the expression and functions of LEF-1 and TCF-1 in peripheral CD4+ T cells and revealed that LEF-1 is dominantly expressed in Th1 but not in Th2 cells. We identified a high affinity LEF-1-binding site in the negative regulatory element of the IL-4 promoter. Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression. This study further confirms a negative regulatory role of LEF-1 in mature peripheral T cells. Furthermore, we found that IL-4 stimulation possesses a negative effect on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive feedback effect of IL-4 on IL4 gene expression.