Glucocorticoids inhibit GATA-3 activity in T cells

ANA C. LIBERMAN; JIMENA DRUKER; DAMIAN REFOJO; FLORIAN HOLSBOER; EDUARDO ARZT

EUROPEAN JOURNAL OF IMMUNOLOGY

Año: 2007

0014-2980

Glucocorticoids (GCs) immunosuppression and anti-inflammatory action involves the regulation of several transcription factors (TF), including, AP-1, NF-kB, NFAT and STAT family members. GCs inhibit the acute production of both Th1 and Th2 cytokines but ultimatly favors a shift towards Th2 phenotype. GATA-3 TF is the master driver of Th2 differentiation. In this study we examined GC regulation of GATA-3. We found that GCs inhibit GATA-3 transcriptional activity. We show that the mechanism underlying GATA-3 inhibition does not involve physical interaction between the glucocorticoid receptor (GR) and GATA-3 nor in vitro reduction of GATA-3 binding to DNA. Instead, we demonstrate that GCs inhibit phosphorylation of GATA-3 by PKA/p38 mitogen activated protein kinases (MAPKs). As an alternative mechanism GCs also inhibit GATA-3 both at mRNA and protein expression levels. Finally, we examined the functional consequences of GATA-3 inhibition by GCs on interleuquin-5 (IL-5) gene, a cytokine central to the pathogenesis of asthmatic airway inflammation, showing that GCs inhibition of GATA-3 activity impacts on this promoter. In view of the crucial role of GATA-3 in T cell differentiation, inflammation and also in asthma pathogenesis we propose that GATA-3 inhibition by GCs may be an important mechanism underlying the anti-inflammatory properties of GCs and also could enable the development of specific inhibitors that lack the side effects of GCs in asthma treatment.