title: LEF-1 negatively controls interleukin-4 expression through a proximal promoter regulatory element.
abstract: 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.
authors.affiliation: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hebenstreit
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.forename: Monika K
authors.initials: MK
authors.lastname: Treiber
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Zhang
authors.forename: Huai-Feng
authors.initials: HF
authors.lastname: Mi
authors.forename: Jutta
authors.initials: J
authors.lastname: Horejs-Hoeck
authors.forename: Kristian G
authors.initials: KG
authors.lastname: Andersen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Albert
authors.initials: A
authors.lastname: Duschl
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D015458:Leukemia, T-Cell; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*
chemical_list: C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D038621:Regulatory Sequences, Ribonucleic Acid; D015847:Interleukin-4