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

Vago, Juliana P.; Tavares, Luciana P.; Garcia, Cristiana C.; Lima, Kátia M.; Perucci, Luíza Oliveira; Vieira, Érica Leandro Marciano; Nogueira, Camila R. C.; Soriani, Frederico Marianetti; Martins, Joilson O.; Silva, Patrícia M.R.; Gomes, Karina Braga; Pinho, Vanessa; Bruscoli, Stefano; Riccardi, Carlo; Beaulieu, Élaine; Morand, Eric Francis; Teixeira, Mauro Martins; Sousa, Lirlândia P.

doi:10.4049/jimmunol.1401722

Cited by 84 publications

(107 citation statements)

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“…Previously published results have demonstrated that Anxa1-KO mice show a high degree of neutrophil recruitment in a zymosan model of peritonitis, which supports its important role in migration (44). Anxa1 is a pivotal protein in the migration process as well as in the resolution phase of inflammation, and a regulatory relationship between Anxa1 and GILZ has been previously suggested (33). In the present study, we found that GILZ is indispensable for the up-regulation of Anxa1 expression by GCs in neutrophils, as evidenced by the lack of Anxa1 up-regulation in GILZ-KO cells.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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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“…(26,27,31). The gating strategy was performed as shown previously (26). LPS injection increased the number of M1 macrophages as previously shown (31), which was decreased with SIV treatment (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Taken together, these findings indicate that elastase inhibitors can effectively induce or accelerate a proapoptotic program in neutrophils leading to resolution of inflammation. (26,27,31). The gating strategy was performed as shown previously (26).…”

Section: Resultsmentioning

confidence: 99%

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Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Vago

Tavares

Sugimoto

et al. 2016

The Journal of Immunology

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Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties. Intact AnxA1 is a 37-kDa protein that may be cleaved in vivo at the N-terminal region by neutrophil proteases including elastase and proteinase-3, generating the 33-kDa isoform that is largely inactive. In this study, we investigated the dynamics of AnxA1 expression and the effects of synthetic (sivelestat [SIV]; Eglin) and natural (secretory leukocyte protease inhibitor [SLPI]; Elafin) protease inhibitors on the resolution of LPS-induced inflammation. During the settings of LPS inflammation AnxA1 cleavage associated closely with the peak of neutrophil and elastase expression and activity. SLPI expression increased during resolving phase of the pleurisy. Therapeutic treatment of LPS-challenge mice with recombinant human SLPI or Elafin accelerated resolution, an effect associated with increased numbers of apoptotic neutrophils in the pleural exudates, inhibition of elastase, and modulation of the survival-controlling proteins NF-κB and Mcl-1. Similar effects were observed with SIV, which dose-dependently inhibited neutrophil elastase and shortened resolution intervals. Mechanistically, SIV-induced resolution was caspase-dependent, associated to increased levels of intact AnxA1 and decreased expression of NF-κB and Mcl-1. The proresolving effect of antiproteases was also observed in a model of monosodium urate crystals–induced inflammation. SIV skewed macrophages toward resolving phenotypes and enhanced efferocytosis of apoptotic neutrophils. A neutralizing antiserum against AnxA1 and a nonselective antagonist of AnxA1 receptor abolished the accelerated resolution promoted by SIV. Collectively, these results show that elastase inhibition not only inhibits inflammation but actually promotes resolution, and this response is mediated by protection of endogenous intact AnxA1 with ensuing augmentation of neutrophil apoptosis.

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“…In monocytes and macrophages, GILZ can be induced by anti-inflammatory agents, such as GCs and interleukin 4 (IL-4) or IL-10 (15,(25)(26)(27). GILZ overexpression in macrophage-like THP-1 cells resulted in GC-like effects, i.e.…”

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confidence: 99%

Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages

Hoppstädter

Hachenthal

Valbuena-Perez

et al. 2016

Journal of Biological Chemistry

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GILZ (glucocorticoid-induced leucine zipper) is inducible by glucocorticoids and plays a key role in their mode of action. GILZ attenuates inflammation mainly by inhibition of NF-B and mitogen-activated protein kinase activation but does not seem to be involved in the severe side effects observed after glucocorticoid treatment. Therefore, GILZ might be a promising target for new therapeutic approaches. The present work focuses on the natural product curcumin, which has previously been reported to inhibit NF-B. GILZ was inducible by curcumin in macrophage cell lines, primary human monocyte-derived macrophages, and murine bone marrow-derived macrophages. The up-regulation of GILZ was neither associated with glucocorticoid receptor activation nor with transcriptional induction or mRNA or protein stabilization but was a result of enhanced translation. Because the GILZ 3-UTR contains AU-rich elements (AREs), we analyzed the role of the mRNA-binding protein HuR, which has been shown to promote the translation of ARE-containing mRNAs. Our results suggest that curcumin treatment induces HuR expression. An RNA immunoprecipitation assay confirmed that HuR can bind GILZ mRNA. In accordance, HuR overexpression led to increased GILZ protein levels but had no effect on GILZ mRNA expression. Our data employing siRNA in LPS-activated RAW264.7 macrophages show that curcumin facilitates its anti-inflammatory action by induction of GILZ in macrophages. Experiments with LPS-activated bone marrow-derived macrophages from wild-type and GILZ knock-out mice demonstrated that curcumin inhibits the activity of inflammatory regulators, such as NF-B or ERK, and subsequent TNF-␣ production via GILZ. In summary, our data indicate that HuR-dependent GILZ induction contributes to the anti-inflammatory properties of curcumin.The polyphenol curcumin (diferuloylmethane) is the principal bioactive compound of turmeric (Curcuma longa) preparations, which are commonly used as traditional remedies or spices. Recently, extensive research has shown that curcumin has a broad range of therapeutic effects, including anti-inflammatory, anti-oxidant, anti-proliferative, hypoglycemic, lipidlowering, anti-thrombotic, and anti-coagulant activity. At the same time, no dose-limiting toxicity was observed in clinical trials, indicating pharmacological safety. Thus, curcumin administration has been suggested as a potential therapeutic approach for the treatment of several pathologic conditions, especially inflammatory diseases such as cardiovascular pathologies, arthritis, asthma, ulcerative colitis, inflammatory bowel disease, and type II diabetes (1-5). Several in vivo studies suggested a profound effect of curcumin on cells of the mononuclear phagocyte system. In a mouse model of abdominal aortic aneurysms, oral administration of curcumin efficiently suppressed mononuclear inflammation in the aortic walls, i.e. proinflammatory cytokine expression and adverse connective tissue remodeling (6). In addition, curcumin decreased the number of proinflammatory M1 macro...

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

Cited by 84 publications

References 51 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

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages

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