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

Abstract

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

GILZ restrains neutrophil activation by inhibiting the MAPK pathway

“…B). The absence of GILZ in the GILZ‐KO mice does not result in any differences in the expression of specific neutrophil surface markers, as previously demonstrated . Nevertheless, we found that, under in vitro experimental settings, GILZ‐KO neutrophils are characterized by increased phagocytosis, killing activity, and oxidative burst.…”

“…In the innate immune cell compartment, GILZ was up‐regulated in alveolar macrophages in a model of LPS tolerance, and GILZ‐deficient macrophages displayed higher responsiveness toward LPS due to increased ERK activation . In human neutrophils, GILZ promotes apoptosis, whereas we have demonstrated that GILZ is necessary for inhibiting glucocorticoids‐induced neutrophil migration to sites of inflammation . At molecular level, GILZ can homo‐ and heterodimerize with partner proteins, including NF‐κB, thereby inhibiting the transcription of downstream pro‐inflammatory mediators .…”

“…RT‐qPCR was performed as previously described . A TaqMan Gene Expression Master Mix was used to detect IL‐1β, IL‐12a, TNF‐α, and IL‐6; SYBR Green Master Mix (Thermo Fisher Scientific) was used to detect β‐actin and GILZ.…”

Elevated expression of glucocorticoid-induced leucine zipper in placental endothelial and trophoblastic cells in preeclampsia

“…[14] GILZ's roles in mediating anti-inflammatory effects of glucocorticoids are shown invariouscell types. [15][16][17] GILZ gene is released in the effect of glucocorticoids. [15][16][17] Some studies have shown that GILZ protein suppresses intracellular NF-KB signaling pathway activation and hampers inflammation in human endothelial cells.…”

“…[15][16][17] GILZ gene is released in the effect of glucocorticoids. [15][16][17] Some studies have shown that GILZ protein suppresses intracellular NF-KB signaling pathway activation and hampers inflammation in human endothelial cells. [17] This shows that GILZ is secreted in large amounts in human tissues and it plays an important role in inflammation.…”