LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the
            <i>Tsc22d3</i>
            gene on the X chromosome

Pinheiro, Iris; Dejager, Lien; Πέττα, Ιωάννα; Vandevyver, Sofie; Puimège, Leen; Mahieu, Tina; Ballegeer, Marlies; Hauwermeiren, Filip Van; Riccardi, Carlo; Vuylsteke, Marnik; Libert, Claude

doi:10.1002/emmm.201201683

Cited by 57 publications

(54 citation statements)

References 54 publications

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“…For instance, TAT-GILZ administration promoted a protective effect in a model of inflammatory bowel disease (9) and spinal cord injury (12). Moreover, recent studies showed that GILZ overexpression inhibits endothelial cell adhesion function (42) and protects against endotoxemia (43) and arthritis (13).…”

Section: Discussionmentioning

confidence: 99%

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

Vago

Tavares

Garcia

et al. 2015

The Journal of Immunology

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108

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Glucocorticoid (GC)-induced leucine zipper (GILZ) has been shown to mediate or mimic several actions of GC. This study assessed the role of GILZ in self-resolving and GC-induced resolution of neutrophilic inflammation induced by LPS in mice. GILZ expression was increased during the resolution phase of LPS-induced pleurisy, especially in macrophages with resolving phenotypes. Pretreating LPS-injected mice with trans-activator of transcription peptide (TAT)–GILZ, a cell-permeable GILZ fusion protein, shortened resolution intervals and improved resolution indices. Therapeutic administration of TAT-GILZ induced inflammation resolution, decreased cytokine levels, and promoted caspase-dependent neutrophil apoptosis. TAT-GILZ also modulated the activation of the survival-controlling proteins ERK1/2, NF-κB and Mcl-1. GILZ deficiency was associated with an early increase of annexin A1 (AnxA1) and did not modify the course of neutrophil influx induced by LPS. Dexamethasone treatment resolved inflammation and induced GILZ expression that was dependent on AnxA1. Dexamethasone-induced resolution was not altered in GILZ−/− mice due to compensatory expression and action of AnxA1. Our results show that therapeutic administration of GILZ efficiently induces a proapoptotic program that promotes resolution of neutrophilic inflammation induced by LPS. Alternatively, a lack of endogenous GILZ during the resolution of inflammation is compensated by AnxA1 overexpression.

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Section: Discussionmentioning

confidence: 99%

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

Vago

Tavares

Garcia

et al. 2015

The Journal of Immunology

Self Cite

108

View full text Add to dashboard Cite

show abstract

“…The effect was similar to dexamethasone, as quantitated by reduced pro-inflammatory Th1 cytokines, IFN-γ, and TNF-α23. Also, TAT-GILZ protected mice against LPS-induced endotoxemia24. An immunomodulatory GILZ-derived peptide ameliorated experimentally autoimmune encephalomyelitis18 and more recently it was reported that deficiency of GILZ in mice resulted in augmented inflammation after IMQ treatment, demonstrating that GILZ plays a T-cell intrinsic role limiting pathogenic Th17 responses in the context of psoriasis25.…”

mentioning

confidence: 82%

Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1

Carceller

Ballegeer

Deckers

et al. 2016

Sci Rep

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Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23–Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il-23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-β1-mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects.

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“…Furthermore, some GC mediated anti-inflammatory effects are shown to be mediated by GILZ via modulation of MAPK pathways resulting in repression of inflammation (Clark and Lasa, 2003;Ayroldi and Riccardi, 2009). In detail, in macrophages and T-cells GILZ inhibits NF-κB function by binding to the p65 subunit and thereby preventing transcription of NF-κB dependent genes (Ayroldi et al, 2001;Pinheiro et al, 2013). Another GR dimer-dependent anti-inflammatory acting gene is ANXA1, coding for Annexin1 (Hannon et al, 2003;Clark, 2007).…”

Section: Gr Induced Anti-inflammatory Acting Genesmentioning

confidence: 99%

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Hübner¹,

Dejager²,

Libert³

et al. 2015

Biological Chemistry

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Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNAbound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of antiinflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile.

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LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome

Cited by 57 publications

References 54 publications

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

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