Novel p65 Binding Glucocorticoid-induced Leucine Zipper Peptide Suppresses Experimental Autoimmune Encephalomyelitis

Srinivasan, Mythily; Janardhanam, Srihari

doi:10.1074/jbc.m111.279257

Cited by 58 publications

(70 citation statements)

References 45 publications

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“…We observed that inhibition of GILZ expression via systemically administered small interfering RNA (siRNA) increased disease severity in murine collagen-induced arthritis, via a mechanism associated with increased proinflammatory cytokine production by phagocytic cells (15). Concordantly, a recent study showed that administration of a GILZ peptide inhibits disease development in the experimental autoimmune encephalomyelitis model of multiple sclerosis, in part via effects on T cell activation (11). Together, these findings demonstrate a suppressive role of GILZ in the regulation of immune cell activation.…”

mentioning

confidence: 66%

“…Subsequent studies showed that GILZ has the capacity to modulate several important proinflammatory-signaling pathways. Most prominently, studies in T lymphocytes demonstrated that GILZ inhibits the nuclear translocation of the p65 subunit of the transcription factor NF-kB, thereby reducing NF-kB transcriptional activity (8)(9)(10)(11). GILZ was also observed to inhibit activation of the AP-1 transcription factor and to interact with Raf-1/Ras, leading to suppression of downstream ERK MAPK activation (12)(13)(14).…”

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confidence: 98%

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

Cheng

Fan

Ngo

et al. 2013

The Journal of Immunology

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Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF-stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-κB activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-κB p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-κB p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment.

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confidence: 66%

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confidence: 98%

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

Cheng

Fan

Ngo

et al. 2013

The Journal of Immunology

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“…These mechanisms are thought to be important for their ability to attenuate inflammation (8). GILZ appears to have a physiological role in the regulation of inflammatory mechanisms; however, there are few reports that explore its role in inflammatory disease (9)(10)(11)(12)(13).…”

Section: R Esolution Of Inflammation Is An Active and Continuousmentioning

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

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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“…GILZ mainly exerts its effects by homo-or heterodimerization with specific partner proteins, including transcription factors, such as NF-kB, and Ras/Raf. The homo-and heterodimers formed then regulate expression of target genes at the transcription level (10)(11)(12)(13).…”

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confidence: 99%

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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Novel p65 Binding Glucocorticoid-induced Leucine Zipper Peptide Suppresses Experimental Autoimmune Encephalomyelitis

Cited by 58 publications

References 45 publications

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

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

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

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

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