Transcriptional Regulation of the Mouse IL-7 Receptor α Promoter by Glucocorticoid Receptor

Abstract

Expression of the IL-7R α-chain (IL-7Rα) is strictly regulated during the development and maturation of lymphocytes. Glucocorticoids (GC) have pleiotypic effects on the growth and function of lymphocytes. Although GC have been reported to induce the transcription of IL-7Rα gene in human T cells, its molecular mechanism is largely unknown. In this study, we show that GC up-regulate the levels of IL-7Rα mRNA and protein in mouse T cells. This effect does not require protein synthesis de novo, because protein synthesis inhibitors do not block the process. Mouse IL-7Rα promoter has striking homology with human and rat, containing consensus motifs of Ikaros, PU.1, and Runx1 transcription factors. In addition, a conserved noncoding sequence (CNS) of ∼270 bp was found 3.6-kb upstream of the promoter, which was designated as CNS-1. A GC receptor (GR) motif is present in the CNS-1 region. Importantly, we show by reporter assay that the IL-7Rα promoter has specific transcription activity in T cells. This activity highly depends on the PU.1 motif. Furthermore, GC treatment augments the transcriptional activity through the GR motif in the CNS-1 region. We also demonstrate that GR binds to the GR motif by EMSA. In addition, by chromatin immunoprecipitation assay, we show that GR is rapidly recruited to endogenous CNS-1 chromatin after GC stimulation. These results demonstrate that GR binds to the GR motif in the CNS-1 region after GC stimulation and then activates the transcription of the IL-7Rα promoter. Thus, this study identifies the IL-7Rα CNS-1 region as a GC-responsive element.

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

“…1, A and B). These results parallel those previously obtained using the transformed murine T cell line KKF, which responds to Dex by up-regulating IL-7R␣ protein expression (16). Dex treatment induces nuclear localization and binding of the glucocorticoid receptor transcription factor to an evolutionarily conserved region 3.5 kb upstream of the transcriptional start site of the Il7r gene (16).…”

“…GR binds to a putative Il7r enhancer in an evolutionarily conserved sequence 3.5 kb upstream of the transcriptional start site (16). The GR site in this evolutionarily conserved sequence is 50 base pairs away from a FoxO1 transcription factor binding site, which positively regulates gene expression in both naive CD4 ϩ and CD8 ϩ T cells (20,21).…”

Formation of IL-7Rαhigh and IL-7Rαlow CD8 T Cells during Infection Is Regulated by the Opposing Functions of GABPα and Gfi-1

“…Some ␥ c chain cytokines and steroids have also been found to regulate IL-7R␣ expression (13,23,24,26). IL-7 and several other ␥ c chain cytokines induce rapid IL-7R␣ down-regulation that is transient in nature because the T cells quickly regain IL-7R␣ expression following removal from high-dose cytokine exposure (23,24).…”

“…Currently, most evidence suggests that control of IL-7R␣ expression in T cells is mediated primarily through changes in Il7ra gene transcription (12,13,22,23), but very few of the mechanistic details of this process are known. Multiple signals can affect Il7ra transcription in T cells, including IL-7 (23), IL-2 (24), and TCR signaling that represses (13,25) and glucocorticoids (13,26) that induce Il7ra transcription. In addition, a few transcription factors have been identified that directly bind to and control Il7ra expression.…”

Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB

“…Nuclear extract was prepared as described in ref. 35. Nuclear extract (5 g) was incubated for 20 min at room temperature with 2 ng of labeled oligonucleotide probe in 10 l of binding buffer [20 mM Tris⅐HCl (pH 7.5)/0.1 mM EDTA/4 mM DTT/40 mM NaCl/0.05% BSA/10% glycerol/0.125% Nonidet P-40) containing 1 g of poly(dI⅐dC).…”