Glucocorticoids: Inflammation and Immunity

Petrillo, Maria Grazia; Bortner, Carl D.; Cidlowski, John A.

doi:10.1007/978-3-319-45950-9_3

Cited by 10 publications

(11 citation statements)

References 142 publications

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“…The GR contains an N-terminal regulatory domain, central DNA binding domain, hinge region and C-terminal ligand binding domain (35–37). The GRα is located in the cytoplasm and forms a complex with several proteins including heat shock protein 70 and 90 (38). Upon ligand binding, GRα is released from this complex and can interact with cytoplasmic signal transduction molecules or translocate to the nucleus.…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

“…The main mechanisms via which GC drive the transcription and regulation of multiple genes are direct DNA binding, tethering and composite binding (38–40) (Figure 1). In the nucleus, GRα is able to modulate gene transcription through binding to target sequences termed GC-response elements (GREs), largely in the cis-regulatory region of target genes (41).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

“…The binding of the GRα to the GRE can also cause conformational changes in the GR which causes the recruitment of cofactors and coregulators to the site with the ability to modulate and alter the transcriptional rate of many target genes (35, 37). Direct DNA binding of the GRα to GREs results in the induction of gene expression and causes the transcription of multiple genes, including anti-inflammatory genes such as IL-10 and IL-1 receptor antagonist (38, 40) as well as GC-induced leucine zipper (GILZ). GRα can also directly bind to negative GREs (nGRE), which results in suppression of the transcription of several proinflammatory modulators and cytokines including interleukin (IL)-1β (38, 40, 42).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

“…Direct DNA binding of the GRα to GREs results in the induction of gene expression and causes the transcription of multiple genes, including anti-inflammatory genes such as IL-10 and IL-1 receptor antagonist (38, 40) as well as GC-induced leucine zipper (GILZ). GRα can also directly bind to negative GREs (nGRE), which results in suppression of the transcription of several proinflammatory modulators and cytokines including interleukin (IL)-1β (38, 40, 42). Another form of gene repression, termed tethering, is mediated by the ability of GRs to tether to pro-inflammatory transcription factors such as the p65 subunit of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), antagonizing their function (35, 43–45).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

“…Additional factors also influence the ability of GRα to regulate gene transcription such as chromatin structure, epigenetic regulators, proximity to the TATA box, and indirect activation of target genes (38, 41). Next to the genomic actions of GRα, it also affects cellular function through non-genomic mechanisms, including suppression of mitogen activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways and activation of proteins with SRC homology 3 [SH3] domains (46) (Figure 1).…”

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

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Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

2019

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Glucocorticoids (GC) are used globally to treat autoimmune and inflammatory disorders. Their anti-inflammatory actions are mainly mediated via binding to the glucocorticoid receptor (GR), creating a GC/GR complex, which acts in both the cytoplasm and nucleus to regulate the transcription of a host of target genes. As a result, signaling pathways such as NF-κB and AP-1 are inhibited, and cell activation, differentiation and survival and cytokine and chemokine production are suppressed. However, the gene regulation by GC can also cause severe side effects in patients. Systemic lupus erythematosus (SLE or lupus) is a multisystem autoimmune disease, characterized by a poorly regulated immune response leading to chronic inflammation and dysfunction of multiple organs, for which GC is the major current therapy. Long-term GC use, however, can cause debilitating adverse consequences for patients including diabetes, cardiovascular disease and osteoporosis and contributes to irreversible organ damage. To date, there is no alternative treatment which can replicate the rapid effects of GC across multiple immune cell functions, effecting disease control during disease flares. Research efforts have focused on finding alternatives to GC, which display similar immunoregulatory actions, without the devastating adverse metabolic effects. One potential candidate is the glucocorticoid-induced leucine zipper (GILZ). GILZ is induced by low concentrations of GC and is shown to mimic the action of GC in several inflammatory processes, reducing immunity and inflammation in in vitro and in vivo studies. Additionally, GILZ has, similar to the GC-GR complex, the ability to bind to both NF-κB and AP-1 as well as DNA directly, to regulate immune cell function, while potentially lacking the GC-related side effects. Importantly, in SLE patients GILZ is under-expressed and correlates negatively with disease activity, suggesting an important regulatory role of GILZ in SLE. Here we provide an overview of the actions and use of GC in lupus, and discuss whether the regulatory mechanisms of GILZ could lead to the development of a novel therapeutic for lupus. Increased understanding of the mechanisms of action of GILZ, and its ability to regulate immune events leading to lupus disease activity has important clinical implications for the development of safer anti-inflammatory therapies.

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Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

Section: The Mechanism Of Gc Action In the Treatment Of Slementioning

confidence: 99%

See 3 more Smart Citations

Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

2019

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Evaluation of stress response in black-tailed prairie dogs (Cynomys ludovicianus) in arid regions from colonies in Chihuahua Mexico

Hernández

Ávila‐Flores

Villa-Meza³

et al. 2023

General and Comparative Endocrinology

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Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

et al. 2022

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Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2–9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

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Glucocorticoids: Inflammation and Immunity

Cited by 10 publications

References 142 publications

Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?

Evaluation of stress response in black-tailed prairie dogs (Cynomys ludovicianus) in arid regions from colonies in Chihuahua Mexico

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

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