Abstract
AbstractInterleukin-2 (IL-2) withdrawal is a physiologic process inducing cell death in activated T lymphocytes. Glucocorticoid-induced leucine zipper (GILZ) has recently been identified as a protein modulating T-cell receptor activation by repressing various signaling pathways. We report here that IL-2 deprivation leads to expression of GILZ in T lymphocytes. We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal. To assess the functional consequences of this induction, we used 2 strategies, GILZ overexpression and GILZ silencing in murine IL-2–dependent CTLL-2 cells. GILZ overexpression protects CTLL-2 cells from IL-2 withdrawal–induced apoptosis, whereas cell death is accelerated in cells unable to express GILZ. Concomitantly, the expression of Bim is inhibited in GILZ-overexpressing cells and enhanced when GILZ expression is impaired. Furthermore, GILZ inhibits FoxO3 transcriptional activity that leads to inhibition of Bim expression but also to down-regulation of GILZ itself. Therefore, GILZ is a transiently expressed protein induced upon IL-2 withdrawal that protects T cells from the onset of apoptosis.
Highlights
Introduction sive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal
Glucocorticoid-induced leucine zipper (GILZ) has been reported to inhibit T-cell receptor (TCR)-induced nuclear factor B (NFB) activation and nuclear translocation by interacting directly with p65/p52.13 GILZ affects the pathway leading to activated protein 1 (AP-1) activation through proteinprotein interactions with c-Fos and c-Jun, and with Raf-1 leading to inhibition of its activity.[14,15]
GILZ expression was undetectable at the protein level at the time of deprivation, a low level of gilz mRNA was detectable by Reverse transcription (RT)-polymerase chain reaction (PCR)
Summary
Introduction sive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal. Brunet et al[7] were the first to ascribe a role to FoxO proteins in programmed cell death, reporting that overexpression of a constitutive active form of FoxO3 induces apoptosis of Jurkat T cells in a Fas-dependent manner. Fas-independent mechanisms of apoptosis induced by FoxO proteins have been observed in other cell lines.[8] FoxO3 has been shown to play a role in apoptosis induced upon cytokine withdrawal in lymphocytes through up-regulation of Bim, a proapoptotic member of the Bcl-2 family.[8,9,10,11]. Overexpression of GILZ in the murine lymphoid 3 DO cell line inhibits anti-CD3–induced apoptosis via down-regulation of Fas/FasL expression and significantly affects IL-2 production and IL-2 receptor expression.[13] GILZ may exert its effects by interfering at various stages of the signaling pathways that are triggered by TCR stimulation. GILZ has been reported to inhibit TCR-induced nuclear factor B (NFB) activation and nuclear translocation by interacting directly with p65/p52.13 GILZ affects the pathway leading to activated protein 1 (AP-1) activation through proteinprotein interactions with c-Fos and c-Jun, and with Raf-1 leading to inhibition of its activity.[14,15] Gilz transcripts are induced upon treatment with glucocorticoid (GC) in lymphoid cells[12] and upon IL-4, IL-10, or GC treatment in monocyte/macrophage cells.[16]
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