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      GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids

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          Glucocorticoid-induced leucine zipper (GILZ) is a dexamethasone-inducible gene that mediates glucocorticoid (GC) actions in a variety of cell types, including many cells of immune system. In particular, GILZ can control T cell activities, such as activation and differentiation, mainly through its ability to homo- and hetero-dimerize with partner proteins, such as NF-κB, Ras, and C/EBP. These protein–protein interactions control the regulation of pro-inflammatory target genes. A number of in vitro and in vivo studies using mouse models of inflammatory diseases demonstrate an anti-inflammatory role for GILZ. Here, authors summarize the studies that make GILZ eligible as an anti-inflammatory protein through which GCs can act. These findings permit the future development of pharmacological tools that mimic the therapeutic effects of GCs while avoiding the detrimental ones.

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          Most cited references 38

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          A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death.

          By comparing mRNA species expressed in dexamethasone (DEX)-treated and untreated murine thymocytes, we have identified a gene, glucocorticoid-induced leucine zipper (GILZ), encoding a new member of the leucine zipper family. GILZ was found expressed in normal lymphocytes from thymus, spleen, and lymph nodes, whereas low or no expression was detected in other nonlymphoid tissues, including brain, kidney, and liver. In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX. Furthermore, GILZ expression selectively protects T cells from apoptosis induced by treatment with anti-CD3 monoclonal antibody but not by treatment with other apoptotic stimuli. This antiapoptotic effect correlates with inhibition of Fas and Fas ligand expression. Thus, GILZ is a candidate transcription factor involved in the regulation of apoptosis of T cells.
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            Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action.

            Glucocorticoids (GCs) represent the mainstay of current anti-inflammatory and immunosuppressive strategies, mediating effects that mostly result in transcriptional regulation of glucocorticoid receptor target genes. A variety of actions are tied together in the response to GC treatment. Dissecting the beneficial from the detrimental actions in GC therapy is a major challenge in basic research, raising the critical issue of whether a single target gene or gene family might eventually be linked to a specific GC function. Glucocorticoid-induced leucine zipper (GILZ) was originally discovered in studies aimed at characterizing genes targeted by dexamethasone. The first suggestion that GILZ plays an important role in GC immunomodulation came from observations of GILZ up-regulation by GCs, mainly in lymphoid organs, and inhibition of anti-CD3-induced activation and apoptosis. The identification of GILZ interaction with and inhibition of NF-kappaB provided a first molecular mechanistic basis for explaining GILZ effects on T cells. Subsequently, other GILZ targets have been identified, including AP-1, Raf-1, and Ras, all involved in GC effects. The finding that GILZ silencing abrogates the antiproliferative activity of dexamethasone and reduces GC inhibition of cytokine-induced COX-2 expression clearly gained GILZ a distinguished reputation within the critical mediators of GC effects. The multiple functions of GILZ and their potential biological relevance are here reviewed.
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              Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB.

              Previously a novel gene was identified that encodes a glucocorticoid-induced leucine zipper (GILZ) whose expression is up-regulated by dexamethasone. This study analyzed the role of GILZ in the control of T-cell activation and its possible interaction with nuclear factor kappaB (NF-kappaB). Results indicate that GILZ inhibits both T-cell receptor (TCR)-induced interleukin-2/interleukin-2 receptor expression and NF-kappaB activity. In particular, GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. Moreover, GILZ-mediated modulation of TCR-induced responses is part of a circuit because TCR triggering down-regulates GILZ expression. These results identify a new molecular mechanism involved in the dexamethasone-induced regulation of NF-kappaB activity and T-cell activation. (Blood. 2001;98:743-753)

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                09 November 2015
                : 6
                1Section of Pharmacology, Department of Medicine, University of Perugia , Perugia, Italy
                Author notes

                Edited by: Isaias Glezer, Universidade Federal de São Paulo, Brazil

                Reviewed by: John Anthony Cidlowski, National Institutes of Health, USA; Omar Tliba, Thomas Jefferson University, USA

                *Correspondence: Carlo Riccardi, carlo.riccardi@ 123456unipg.it

                Specialty section: This article was submitted to Cellular Endocrinology, a section of the journal Frontiers in Endocrinology

                Copyright © 2015 Ronchetti, Migliorati and Riccardi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 42, Pages: 6, Words: 4154
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                Endocrinology & Diabetes

                glucocorticoids, gilz, inflammation, immune cells, transcription factor


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