The role of the glucocorticoid receptor in inflammation and immunity

Baschant, Ulrike; Tuckermann, Jan

doi:10.1016/j.jsbmb.2010.03.058

Cited by 306 publications

(229 citation statements)

References 82 publications

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“…GCs play essential roles in the body's adaptation to hypoxic environments and in homeostasis maintenance by regulating the expression of genes (15,16) and have therefore been widely used to treat the high mountain sickness (16,17) and severe tissue damage due to hypoxia and ischemia (18,19). The effect of GC is due, at least in part, to its immunosuppressive and anti-inflammatory effects (20,21). Most of the anti-inflammatory effects of GC are mediated by GC receptor (GR), which can modulate gene expression through either a direct interaction with GC response element in the promoter region of target genes (22) or an interference with other transcription factors, such as NF-kB and AP-1, to inhibit their transcriptional activity (23)(24)(25).…”

mentioning

confidence: 99%

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Wang

Song

et al. 2012

The Journal of Immunology

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Hypoxia and inflammation often develop concurrently in numerous diseases, and the influence of hypoxia on natural evolution of inflammatory responses is widely accepted. Glucocorticoid-induced leucine zipper (GILZ) is thought to be an important mediator of anti-inflammatory and immune-suppressive actions of glucocorticoid (GC). However, whether GILZ is involved in hypoxic response is still unclear. In this study, we investigated the effects of hypoxic exposure and/or the administration of dexamethasone (Dex), a synthetic GC on GILZ expression both in vitro and in vivo, and further explored the relationship between GILZ and proinflammatory cytokines IL-1β, IL-6, and TNF-α under normoxic and hypoxic conditions. We found that hypoxia not only remarkably upregulated the expression of GILZ, but also significantly enhanced Dex-induced expression of GILZ in macrophages and the spleen of rats. ERK activity is found involved in the upregulation of GILZ induced by hypoxia. Inhibiting the expression of GILZ in RAW264.7 cells using specific GILZ small interfering RNA led to a significant increase in mRNA production and protein secretion of IL-1β and IL-6 in hypoxia and abrogated the inhibitory effect of Dex on expression of IL-1β and IL-6 in hypoxia. We also found that adrenal hormones played pivotal roles in upregulation of GILZ expression in vivo. Altogether, data presented in this study suggest that GILZ has an important role not only in adjusting adaptive responses to hypoxia by negatively regulating the activation of macrophages and the expression of proinflammatory cytokines, but also in mediating the anti-inflammatory action of GC under hypoxic conditions.

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mentioning

confidence: 99%

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Wang

Song

et al. 2012

The Journal of Immunology

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“…Dev., 34 (2): 74-81, 2015(Gustafson et al, 2010. The DEX and other glucocorticoids affect growth, differentiation and function of many cell types, such as T cells, macrophages, monocytes and DCs (Baschant and Tuckermann, 2010).…”

Section: Dendriticmentioning

confidence: 99%

Effect of Dexamethasone on Phenotyping of Dendritic Cells: In vitro and in vivo Study

Al-Ashmawy¹,

El-Zamaran²,

El-Ashmawy³

et al. 2015

Science, Technology and Development

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Background: Glucocorticoids are known to suppress the immune response and are widely used as immunosuppressive agents in the treatment of many autoimmune and allergic diseases. Aim: This study investigated the effect of the steroid dexamethasone (DEX) on maturation and differentiation of DCs derived from monocytes. In addition, an in vivo experiment was conducted to investigate whether treatment of mice with DEX has immunomodulatory effect on murine splenic DCs. Methods: In vitro experiment: Immature DCs were generated by incubating peripheral blood monocytes with cytokine cocktail (GM-CSF+IL-4) for 9 days. Phenotypic analysis of the DCs' specific cell marker CD83 was performed by flow cytometry. In vivo experiment: Mice were randomly divided into 5 groups according to the dose of i.p., injection of DEX and duration of treatment. The murine splenic DCs were isolated and phenotyped for CD83 and CD11c by flow cytometry. Results: Addition of 1 µM DEX to the culture on day 7 or 8 resulted in a significant increase in the CD83 expression. The in vivo experiment showed that i.p. injection of DEX significantly increased the expression of CD83 on splenic DCs. Mice groups treated with a single dose of 20 mg kgG 1 DEX showed a significant decrease of percentage of CD11c + CD83 + splenic DCs. Conclusion: DEX induced the DCs to be more tolerogenic both in vitro and in vivo. It could be suggested that DEX can trigger immunosuppressive effect via modulating the expression of the cell surface markers of DCs.

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“…As a liganddependent transcription factor, liganded GR regulates gene expression through either direct interaction with GC response elements (GRE) in the promoter region of target genes (Phuc Le et al 2005, Baschant & Tuckermann 2010 or an interference with other transcription factors to inhibit their transcriptional activity (Kassel & Herrlich 2007, Baschant & Tuckermann 2010. Increasing evidence in tumor models demonstrated that GC could enhance cancer cell resistance to unfavorable microenvironment and chemotherapeutics in epithelial (i.e., 'solid') tumors, which is very important for the progression of cancer (Herr et al 2007), and should be of important clinical relevance when it interferes with the effect of chemotherapeutics.…”

Section: Introductionmentioning

confidence: 99%

The pro-adhesive and pro-survival effects of glucocorticoid in human ovarian cancer cells

Yin

Fang

Song

et al. 2016

Journal of Molecular Endocrinology

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Cell adhesion to extracellular matrix (ECM) is controlled by multiple signaling molecules and intracellular pathways, and is pivotal for survival and growth of cells from most solid tumors. Our previous works demonstrated that dexamethasone (DEX) significantly enhances cell adhesion and cell resistance to chemotherapeutics by increasing the levels of integrin β1, α4, and α5 in human ovarian cancer cells. However, it is unclear whether the components of ECM or other membrane molecules are also involved in the proadhesive effect of DEX in ovarian cancer cells. In this study, we demonstrated that the treatment of cells with DEX did not change the expression of collagens (I, III, and IV), laminin, CD44, and its principal ligand hyaluronan (HA), but significantly increased the levels of intracellular and secreted fibronectin (FN). Inhibiting the expression of FN with FN1 siRNA or blocking CD44, another FN receptor, with CD44 blocking antibody significantly attenuated the pro-adhesion of DEX, indicating that upregulation of FN mediates the pro-adhesive effect of DEX by its interaction with CD44 besides integrin β1. Moreover, DEX significantly enhanced cell resistance to the chemotherapeutic agent paclitaxel (PTX) by activating PI-3K-Akt pathway. Finally, we found that DEX also significantly upregulated the expression of MUC1, a transmembrane glycoprotein. Inhibiting the expression of MUC1 with MUC1 siRNA significantly attenuated the DEX-induced effects of pro-adhesion, Akt-activation, and pro-survival. In conclusion, these results provide new data that upregulation of FN and MUC1 by DEX contributes to DEX-induced pro-adhesion and protects ovarian cancer cells from chemotherapy.

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The role of the glucocorticoid receptor in inflammation and immunity

Cited by 306 publications

References 82 publications

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Effect of Dexamethasone on Phenotyping of Dendritic Cells: In vitro and in vivo Study

The pro-adhesive and pro-survival effects of glucocorticoid in human ovarian cancer cells

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