A New Dexamethasone-Induced Gene of the Leucine Zipper Family Protects T Lymphocytes from TCR/CD3-Activated Cell Death

D'Adamio, F.; Zollo, Ornella; Moraca, R.; Ayroldi, Emira; Bruscoli, Stefano; Bartoli, Andréa; Cannarile, Lorenza; Migliorati, Graziella; Riccardi, Carlo

doi:10.1016/s1074-7613(00)80398-2

Cited by 411 publications

(438 citation statements)

References 47 publications

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“…The X‐linked gene Tsc22d3 , also called Gilz (D'Adamio et al ., 1997), encodes a leucine zipper protein that unexpectedly was found to be essential for male fertility. Males hemizygous for a knockout mutation in Tsc22d3 , from three independently generated strains (Bruscoli et al ., 2012; Ngo et al ., 2013a, 2013b; Romero et al ., 2012; Suarez et al ., 2012), are sterile due to the inability of spermatocytes to complete the first meiotic division.…”

Section: Resultsmentioning

confidence: 99%

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Köentgen¹,

Lin

Κατίδου

et al. 2016

Genesis

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SummaryGene targeting in embryonic stem (ES) cells remains best practice for introducing complex mutations into the mouse germline. One aspect in this multistep process that has not been streamlined with regard to the logistics and ethics of mouse breeding is the efficiency of germline transmission: the transmission of the ES cell‐derived genome through the germline of chimeras to their offspring. A method whereby male chimeras transmit exclusively the genome of the injected ES cells to their offspring has been developed. The new technology, referred to as goGermline, entails injecting ES cells into blastocysts produced by superovulated homozygous Tsc22d3 floxed females mated with homozygous ROSA26‐Cre males. This cross produces males that are sterile due to a complete cell‐autonomous defect in spermatogenesis. The resulting male chimeras can be sterile but when fertile, they transmit the ES cell‐derived genome to 100% of their offspring. The method was validated extensively and in two laboratories for gene‐targeted ES clones that were derived from the commonly used parental ES cell lines Bruce4, E14, and JM8A3. The complete elimination of the collateral birth of undesired, non‐ES cell‐derived offspring in goGermline technology fulfills the reduction imperative of the 3R principle of humane experimental technique with animals. genesis 54:326–333, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Köentgen¹,

Lin

Κατίδου

et al. 2016

Genesis

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“…29 Corticosteroids are also known to inhibit T cell receptor (TCR)-mediated activation-induced cell death (AICD), which serves to attenuate T cell responses and promote peripheral T cell deletion. 30,31 In these contexts, corticosteroids may positively influence and help sustain T cell responses to overcome foreign antigens, pathogens, and tumors.…”

Section: Discussionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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“…We have previously identified a gene known as glucocorticoid-induced leucine zipper (GILZ), which is rapidly activated by dexamethasone (DEX), a synthetic GC specific for GR, and inhibits T-lymphocyte activation [15,16]. The GILZ gene encodes various isoforms among which GILZ is the isoform expressed in normal T lymphocytes that mediates some of the immunomodulatory effects of GC, including inhibition of NF-κB activation and nuclear translocation [15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

et al. 2012

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Spinal cord injury (SCI) is a traumatic event that causes a secondary and extended inflammation characterized by infiltration of immune cells, including T lymphocytes, release of pro-inflammatory mediators in the lesion site, and tissue degeneration. Current therapeutic approaches for SCI are limited to glucocorticoids (GC) due to their potent antiinflammatory activity. GC efficacy resides, in part, in the capability to inhibit NF-κB, T lymphocyte activation, and the consequent cytokine production. In this study, we performed experiments aimed to test the susceptibility of glucocorticoidinduced leucine zipper (GILZ) transgenic (GILZ TG ) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ TG were less susceptible to SCI as compared to wild-type littermates. Notably, inhibition of NF-κB activation and nuclear translocation, diminished T lymphocytes activation and tissue infiltration, as well as decreased release of cytokines were evident in GILZ TG as compared to wild-type mice. Moreover, GILZ TG showed a reduced tumor necrosis factor-α, IL-1β, Inductible nitric oxide synthase (iNOS) and nytrotyrosine production, apoptosis, and neuronal tissue damage. Together these results indicate that GILZ mimics the anti-inflammatory effect of GC and represents a potential pharmacological target for modulation of T lymphocyte-mediated immune response in inflammatory disorders, such as SCI.

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A New Dexamethasone-Induced Gene of the Leucine Zipper Family Protects T Lymphocytes from TCR/CD3-Activated Cell Death

Cited by 411 publications

References 47 publications

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

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