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Abstract
Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions.
Highlights
Introduction published maps and institutional affilGlucocorticoid-induced leucine zipper (GILZ) is a gene rapidly transcribed by either endogenous or pharmacologically administered glucocorticoids [1,2,3,4,5]
Since GILZ is one of the most important early-induced genes by glucocorticoids, we aimed to define the role of glucocorticoids in the regulation of Toll-like receptor 2 (TLR2) in neutrophils in wild type (WT) and GILZ knock-out (KO) mice
Downregulated TLR2 in WT but not in the KO mice, suggesting that GILZ was involved in glucocorticoid-mediated downregulation of TLR2
Summary
Introduction published maps and institutional affilGlucocorticoid-induced leucine zipper (GILZ) is a gene rapidly transcribed by either endogenous or pharmacologically administered glucocorticoids [1,2,3,4,5]. Several studies have demonstrated that GILZ exerts anti-inflammatory activity, often acting as a mediator of glucocorticoid actions but without the glucocorticoid-derived side effects [6,7,8,9,10]. GILZ is rapidly induced by glucocorticoids primarily in immune cells of the adaptive and innate system and regulates their cellular functions (e.g., activation, differentiation, and apoptosis) [3,11,12,13,14,15,16]. Within the cells of the innate immune system, few studies have investigated the function of GILZ in neutrophils. Annexin A1 gene transcription in neutrophils, one of the primary and first discovered mechanisms by which glucocorticoids exert their powerful anti-inflammatory effects [17].
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