Glucocorticoids inhibitGATA‐3 phosphorylation and activity in T cells

Abstract

Glucocorticoid (GC) immunosuppression and anti-inflammatory action involve the regulation of several transcription factors (TFs). GCs inhibit the acute production of T-helper (Th) 1 and Th2 cytokines but ultimately favor a shift toward Th2 phenotype. GCs inhibit the transcriptional activity of T-bet Th1 TF by a transrepression mechanism. Here we analyze GC regulation of GATA-3, the master driver of Th2 differentiation. We found that GCs inhibit GATA-3 transcriptional activity. We demonstrate that this mechanism does not involve physical interaction between the glucocorticoid receptor (GR) and GATA-3 or reduction of GATA-3 binding to DNA, as described previously for T-bet. Instead, GCs inhibit GATA-3 activity by inhibition of p38 mitogen-activated protein kinase induced GATA-3 phosphorylation. GCs also inhibit GATA-3 mRNA and protein expression. Finally, GATA-3 inhibition affects the interleukin-5 gene, a central Th2 cytokine. The IC(50) of dexamethasone is 10 nM with a maximum effect at 100 nM. All inhibitory actions were blocked by the GR antagonist RU38486 (1 uM), proving the specificity of GR action. In view of the crucial role of GATA-3 in T-cell differentiation and inflammation, we propose that the mechanism of GATA-3 inhibition compared with that in T-bet may have relevant implications in understanding and modulating the anti-inflammatory and Th-regulatory properties of GCs.

Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells

“…Nonetheless, the unresponsiveness of IL-17A −/− mice to Dex treatment and the reduction of IL-17 levels in WT and IFN-γ −/− mice, but not in GR mutant mice, strongly indicate that IL-17 is a major target for immunosuppression by GCs. GCs are capable of suppressing T H 1 cytokines like IFN-γ and TNF-α by reducing STAT-4 activity through direct interaction, thereby inhibiting the T H 1 lineage-specific transcription factor Tbet (37,38). To date, only a few studies have reported suppressive effects of GCs on T H 17 cells (39)(40)(41).…”

The role of the glucocorticoid receptor in inflammation and immunity

“…The interaction results in diminished binding of T-bet to DNA. [71]. Also the activity of the Th2 defining transcription factor GATA-3 is suppressed by the GR.…”

The Molecular and Cellular Mechanisms Responsible for the Anti-inflammatory and Immunosuppressive Effects of Glucocorticoids

“…Indeed, GCs inhibit both T-bet, which is selectively expressed in Th1 cells, by transrepression, and GATA3, which is selectively expressed in Th2 cells, by inhibiting p38 MAPK phosphorylation. However, the greater sensitivity of T-bet to GC inhibition favors Th2 development, particularly during long-term GC treatment [ 49 ]. The GC-dependent upregulation of Itk, a Tec kinase favoring Th2 polarization, may be another polarization mechanism of GC [ 73 ].…”