GILZ Overexpression Inhibits Endothelial Cell Adhesive Function through Regulation of NF-κB and MAPK Activity

Cheng, Qiang; Fan, Huapeng; Ngo, Devi; Beaulieu, Élaine; Leung, Patrick S.C.; Lo, Camden; Burgess, Rosemary; Zwan, Yvonne G. van der; White, Stefan J.; Khachigian, Levon M.; Hickey, Michael J.; Morand, Eric Francis

doi:10.4049/jimmunol.1202662

Cited by 58 publications

(74 citation statements)

References 47 publications

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“…GILZ is known to homo-or heterodimerize with partner proteins, such as, NF-kB, CCAAT/enhancer binding protein, and Ras, but is unable to bind to DNA to regulate the transcription of target genes (7,13,28,57,58). Our findings on the regulation of Anxa1 expression by GILZ indicate that the control is at the transcription level, which implies the presence of a binding cotranscription factor on the Anxa1 promoter.…”

Section: Discussionmentioning

confidence: 64%

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

et al. 2017

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The glucocorticoid-induced leucine zipper (GILZ) gene is a pivotal mediator of the anti-inflammatory effects of glucocorticoids (GCs) that are known to regulate the function of both adaptive and innate immunity cells. Our aim was to investigate the role of GILZ in GC-induced inhibition of neutrophil migration, as this role has not been investigated before. We found that GILZ expression was induced by dexamethasone (DEX), a synthetic GC, in neutrophils, and that it regulated migration of these cells into inflamed tissues under DEX treatment. Of note, inhibition of neutrophil migration was not observed in GILZ-knockout mice with peritonitis that were treated by DEX. This was because DEX was unable to up-regulate annexin A1 (Anxa1) expression in the absence of GILZ. Furthermore, we showed that GILZ mediates Anxa1 induction by GCs by transactivating Anxa1 expression at the promoter level via binding with the transcription factor, PU.1. The present findings shed light on the role of GILZ in the mechanism of induction of Anxa1 by GCs. As Anxa1 is an important protein for the resolution of inflammatory response, GILZ may represent a new pharmacologic target for treatment of inflammatory

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Section: Discussionmentioning

confidence: 64%

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

et al. 2017

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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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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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“…In addition to its ability to bind to NF-kB and AP-1, GILZ has also been reported to interfere with MAPK signaling (3,7,8,23,30,31). MAPKs modulate various physiological cell processes, such as proliferation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…GILZ has been suggested to modulate MAPK signaling in various cell types (3,7,8,23,30,31). Therefore, we examined LPS-induced p38, JNK, and ERK activation in WT and GILZ KO cells.…”

Section: Sensitization Of Gilz Ko Macrophages Toward Lps Is Facilitatmentioning

confidence: 99%

“…GILZ was first isolated as a dexamethasone-responsive gene from a thymus subtraction library (5). It is widely expressed in many tissues, such as lung, spleen, liver, kidney, brain, heart, and skeletal muscle, as well as in a variety of cells such as macrophages, T lymphocytes, and endothelial cells (1,3,4,6,7).…”

Section: G Lucocorticoid (Gc)-induced Leucine Zipper (Gilz Tsc22d3) mentioning

confidence: 99%

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Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

Hoppstädter

Kessler

Bruscoli

et al. 2015

The Journal of Immunology

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Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.

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GILZ Overexpression Inhibits Endothelial Cell Adhesive Function through Regulation of NF-κB and MAPK Activity

Cited by 58 publications

References 47 publications

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

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

Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

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