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FoxO3 Mediates Antagonistic Effects of Glucocorticoids and Interleukin-2 on Glucocorticoid-Induced Leucine Zipper Expression

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 461 (M.-L.A.-L., A.B.-V., S.K., J.B., M.P.), Faculté de Pharmacie Paris-XI, 92296 Chamacr;tenay-Malabry, France; and INSERM, Unité 478 (M.L.), Faculté de Médecine X. Bichat, 75870 Paris, France

Address all correspondence and requests for reprints to: Marc Pallardy, Institut National de la Santé et de la Recherche Médicale, Unité 461, Faculté de Pharmacie Paris XI, 5 rue Jean-Baptiste Clément, 92296 Chtenay-Malabry Cedex, France. E-mail: marc.pallardy{at}cep.u-psud.fr.

We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs). Promoter deletion analysis and point mutations showed that individual mutation of the GC-responsive elements does not affect GC-induced transcription and that FHRE-1 and FHRE-3 elements contribute to the effects of GCs. Furthermore, overexpression of the Forkhead transcription factor FoxO3 enhances GC-induced gilz mRNA expression. The functional significance of the interaction between FoxO3 and GC receptor was established in T lymphocytes. Indeed, we show that GCs failed to induce GILZ expression in the presence of IL-2, a cytokine known to antagonize GC effects in T cells. Using a constitutive active mutant of protein kinase B that inactivates FoxO3 or a FoxO3 mutant that cannot be inactivated by protein kinase B, we demonstrate that IL-2 inhibitory effects on GILZ expression are mediated through inhibition of FoxO3 transcriptional activity. Therefore, FoxO3 appears to be a key factor mediating GC and IL-2 antagonism for gilz regulation in T lymphocytes. This regulation of GILZ expression was placed in a meaningful context in evaluating the effects of GILZ on GC-induced apoptosis in T lymphocytes.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Ligands:   Dexamethasone

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