Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells

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...

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Detalles Bibliográficos
Autores principales: Liberman, A.C., Druker, J., Refojo, D., Holsboer, F., Arzt, E.
Formato: JOUR
Materias:
GCs
Interleukin 5
p38 mitogen-activated protein kinase
T helper 2
cyclic AMP
dexamethasone
glucocorticoid
glucocorticoid receptor
interleukin 5
messenger RNA
mifepristone
mitogen activated protein kinase p38
transcription factor GATA 3
transcription factor T bet
animal cell
article
cell differentiation
controlled study
DNA binding
genetic transcription
human
human cell
IC 50
mouse
nonhuman
phenotype
priority journal
protein expression
protein phosphorylation
Th2 cell
Animals
Cell Line
Cercopithecus aethiops
COS Cells
Cyclic AMP-Dependent Protein Kinases
Dexamethasone
GATA3 Transcription Factor
Hela Cells
Humans
Hydrocortisone
Immunoprecipitation
Interleukin-5
Mice
Mice, Inbred BALB C
p38 Mitogen-Activated Protein Kinases
Phosphorylation
RNA, Messenger
Signal Transduction
Th2 Cells
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_08926638_v23_n5_p1558_Liberman
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario: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 IC50 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 in-flammation, 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. © FASEB.

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