GILZ promotes production of peripherally induced Treg cells and mediates the crosstalk between glucocorticoids and TGF-β signaling.
Regulatory T (Treg) cells expressing the transcription factor forkhead box P3 (FoxP3) control immune responses and prevent autoimmunity. Treatment with glucocorticoids (GCs) has been shown to increase Treg cell frequency, but the mechanisms of their action on Treg cell induction are largely unknown. Here, we report that glucocorticoid-induced leucine zipper (GILZ), a protein induced by GCs, promotes Treg cell production. In mice, GILZ overexpression causes an increase in Treg cell number, whereas GILZ deficiency results in impaired generation of peripheral Treg cells (pTreg), associated with increased spontaneous and experimental intestinal inflammation. Mechanistically, we found that GILZ is required for GCs to cooperate with TGF-β in FoxP3 induction, while it enhances TGF-β signaling by binding to and promoting Smad2 phosphorylation and activation of FoxP3 expression. Thus, our results establish an essential GILZ-mediated link between the anti-inflammatory action of GCs and the regulation of TGF-β-dependent pTreg production.
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Oxana
O
Bereshchenko
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Maddalena
M
Coppo
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Stefano
S
Bruscoli
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Michele
M
Biagioli
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Monica
M
Cimino
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Tiziana
T
Frammartino
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Daniele
D
Sorcini
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Alessandra
A
Venanzi
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy.
Moises
M
Di Sante
Department of Medicine, Section of Pharmacology, University of Perugia, S. Andrea delle Fratte, Perugia 06132, Italy. Electronic address: carlo.riccardi@unipg.it.
Carlo
C
Riccardi
D000818:Animals; D003093:Colitis, Ulcerative / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C498608:Dsip1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005938:Glucocorticoids; D014157:Transcription Factors; D016212:Transforming Growth Factor beta