Interleukin-13 Gene Expression Is Regulated by GATA-3 in T Cells

Abstract

Using a transgenic approach, we studied the role of GATA-3 in T cells. As previously shown, enforced GATA-3 expression in transgenic mice inhibits Th1 differentiation of CD4 T cells, but unexpectedly, both type 1 (interferon ␥) and type 2 (interleukin (IL)-4 and IL-13) cytokine genes were activated in the transgenic CD8 T cells. Because IL-13 gene expression was highly enhanced in vivo by GATA-3 expression, we studied the human and the mouse IL-13 gene promoters and found an evolutionary-conserved association of a consensus GATA binding site and two GATG motifs. We showed that efficient GATA-3 binding to this regulatory sequence required these three motifs and that the affinity of the GATA zinc fingers for this association was five times higher than for the consensus GATA binding site alone. Transfections in a T cell line or transactivation by GATA-3 showed that the combination of the three sites was required for full transcriptional activity of the IL-13 gene promoter. Finally we showed that this association of binding sites causes a very high sensitivity of the IL-13 gene promoter to small variations in the level of GATA-3 protein. Altogether, these results indicate an important role of GATA-3 in CD8 cytokine gene expression and demonstrate that a critical network of GATA binding sites highly modulates GATA-3 activity.

Essential Role of GATA3 for the Maintenance of Type 2 Helper T (Th2) Cytokine Production and Chromatin Remodeling at the Th2 Cytokine Gene Loci

“…The production of Th2 cytokines, particularly IL-5 and IL-13, were reported to be highly dependent on the transcriptional activity of GATA3 (16,35,36). We reported that expression of GATA3 induced more than a 10-fold increase in IL-5 and IL-13 promoter activities, whereas that of the IL-4 promoter was increased only about 2-fold (23).…”

Interleukin (IL)-4-independent Maintenance of Histone Modification of the IL-4 Gene Loci in Memory Th2 Cells

“…This may account for the great amounts of Th2 cytokine production including IL-13 and IL-5 (Fig. 2), whose transcription is highly sensitive to GATA3 (58,59).…”

CD28 Costimulation Controls Histone Hyperacetylation of the Interleukin 5 Gene Locus in Developing Th2 Cells

“…2 and 3). The transcription of IL-5 and IL-13 is known to be highly dependent on GATA3 as compared with that of IL-4 (11,48,49). An efficient transcription of IL-5 or IL-13 may require the enhanced levels of GATA3 that can be achieved by the presence of CD28-costimulation.…”