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Glucocorticoids inhibitGATA‐3 phosphorylation and activity in T cells
Author(s) -
Liberman Ana C.,
Druker Jimena,
Refojo Damian,
Holsboer Florian,
Arzt Eduardo
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-121236
Subject(s) - transrepression , glucocorticoid receptor , phosphorylation , transcription factor , protein kinase a , glucocorticoid , microbiology and biotechnology , kinase , chemistry , receptor , biology , gene , endocrinology , biochemistry , transactivation
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 inhibitGATA‐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 inhibitGATA‐3 activity by inhibition of p38 mitogen‐ activated protein kinase inducedGATA‐3 phosphorylation. GCs also inhibitGATA‐3 mRNA and protein expression. Finally, GATA‐3 inhibition affects theinterleukin‐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 antiinflammatory and Th‐regulatory properties of GCs.— Liberman, A. C., Druker, J., Refojo, D., Holsboer, F., Arzt, E. Glucocorticoids inhibitGATA‐3 phosphorylation and activity in T cells. FASEBJ. 23, 1558–1571 (2009)