LEF-1 negatively controls interleukin-4 expression through a proximal promoter regulatory element.
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.
Hebenstreit
Daniel
D
Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
Giaisi
Marco
M
Treiber
Monika K
MK
Zhang
Xiao-Bin
XB
Mi
Huai-Feng
HF
Horejs-Hoeck
Jutta
J
Andersen
Kristian G
KG
Krammer
Peter H
PH
Duschl
Albert
A
Li-Weber
Min
M
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*
C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D038621:Regulatory Sequences, Ribonucleic Acid; D015847:Interleukin-4