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Regulatory and Mechanistic Actions of Glucocorticoids on T and Inflammatory Cells

Ana C. Liberman, Maia L. Budziñski, Clara Sokn and 3 more

Frontiers in Endocrinology · 2018 · Review

doi:10.3389/fendo.2018.00235

Abstract

Glucocorticoids (GCs) play an important role in regulating the inflammatory and immune response and have been used since decades to treat various inflammatory and autoimmune disorders. Fine-tuning the glucocorticoid receptor (GR) activity is instrumental in the search for novel therapeutic strategies aimed to reduce pathological signaling and restoring homeostasis. Despite the primary anti-inflammatory actions of GCs, there are studies suggesting that under certain conditions GCs may also exert pro-inflammatory responses. For these reasons the understanding of the GR basic mechanisms of action on different immune cells in the periphery (e.g., macrophages, dendritic cells, neutrophils, and T cells) and in the brain (microglia) contexts, that we review in this chapter, is a continuous matter of interest and may reveal novel therapeutic targets for the treatment of immune and inflammatory response.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Living organisms must sustain a dynamic equilibrium in order to maintain homeostasis and survival which is constantly challenged by internal or external stressors. In order to appropriately cope with stressful stimuli, they have developed a highly conserved regulatory system. This neuroendocrine system consists mainly of the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system. Glucocorticoids (GCs), are the end-product of the HPA axis, and play an important role in the maintenance of both resting and stress-related responses. If the stress response is dysregulated, homeostasis is altered and probably a wide range of adverse effects may appear on many vital physiological functions, such as growth, development, metabolism, reproduction, immune response, cognition, and behavior.

GCs act on almost all types of cells and in particular in the immune cells they have been shown to have powerful immunosuppressive and anti-inflammatory activities. As a result of their anti-inflammatory properties, GCs are widely used to help treat many different conditions, such as allergic, autoimmune, inflammatory, and hematological alterations. Interestingly, an accumulating body of evidence now strongly suggests that GCs can have both pro- and anti-inflammatory roles under specific conditions. The pro-inflammatory activity of GCs is most apparent in the central nervous system (CNS). These opposite effects work together in order to resolve cellular responses to inflammatory stimuli and also as a protective mechanism “priming” the immune cells to efficiently respond to the noxa or stressor and then restore homeostasis.

Upon peripheral or cerebral immune stimulation, the HPA axis is activated. When the immunogenic stress occurs in the brain, local inflammatory components activate the HPA axis. However, if the challenge takes place outside the brain, multiple pathways bring together stimulatory signals from the periphery to the HPA axis. Mounting evidence suggests that cytokine signals access to the brain through different pathways. These pathways mainly include: cytokines passing across the blood–brain barrier; by specific saturable transport molecules on the brain endothelium; activation of endothelial cells of brain capillaries that release second messengers within the brain parenchyma; transmission of cytokine signals via afferent nerve fibers and finally by peripherally activated monocytes that can enter into the brain. The induction of these different mechanisms modulates cytokine activity in the brain.

The accurate regulation of the HPA axis activity is critical, since GC imbalances can result in many different pathological conditions. Long-term treatment with GCs may result in a plethora of harmful undesired side effects, such as diabetes, hypertension, growth retardation, dyslipidemia, osteoporosis, glaucoma, muscle atrophy, and is also related to many important behavioral alterations, among others. Chronic exposure to GCs can also be associated with GC insensitivity, reducing the efficacy of the therapy. Also, alterations or deficits in the HPA axis response are tightly associated with a wide range of autoimmune and inflammatory diseases.

In this review, we will discuss the role of GCs on the immune and inflammatory cells in the periphery and also the physiological importance and mechanisms implicated in the apparent paradoxical functions of GCs in the brain in order to appropriately maintain a coordinated homeostatic response.

The Glucocorticoid Receptor (GR)

As a small lipophilic hormone, GCs can rapidly diffuse into cells and exert their main actions. These actions are elicited by the binding of GCs to their intracellular receptor, the GR. The GR is a hormone-activated transcription factor (TF) that belongs to the superfamily of nuclear hormone receptors. GR is a modular protein composed of three distinct regions with different functions (Figure 1A). The N-terminal domain (NTD) contains a transactivation domain called activation function 1 (AF1) that is responsible for the transcriptional activation and is implicated in the association with coregulators and the basal transcription machinery. The DNA-binding domain (DBD) is composed of two zinc fingers that have been shown to be important for GR homodimerization and DNA-binding specificity. The hinge region, which separates the DBD from the ligand binding domain (LBD), is a flexible linker structure which is implicated in allowing proper DNA binding, dimerization, and nuclear translocation of the receptor. The C-terminal LBD, contains the ligand binding site and a second transactivation domain (AF2) regulated by hormone binding. The AF2 transactivation domain is important for the interaction with co-chaperones, coregulators, and other TFs. The LBD also encompasses a dimer interface which is critical for GR function and the binding of the heat shock protein (Hsp) 90. The DBD and LBD both contain nuclear localization signals, which are important for GR nuclear translocation. The DBD also contains the nuclear export signal sequence (NES) which targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex.

Some degree in the heterogeneity in GR proteins may result from alternative splicing (Figure 1B). The specificity and sensitivity of different target tissues to GCs has been reported to be related to GR isoforms. The GRα is the predominant isoform, and it is the one that transduces GCs signaling in the cell. There are other four additional splice variants identified: GRβ, GRγ, GR-A, and GR-P. GRβ differs from GRα in the carboxy terminal sequence, rendering GRβ non-responsive to GCs, with no transcription of target genes. Therefore, GRβ can be described as a dominant negative inhibitor of GRα activity. GRβ does not bind GC agonists, however, it does bind to the GR antagonist RU-486. GRβ can inhibit GRα transcriptional activity by different molecular mechanisms including competition for glucocorticoid response elements (GRE), interference with the activity of coregulators, and formation of inactive dimers. In most tissues, GRβ is expressed at very low levels. However, abundant GRβ expression has been described especially in some inflammatory cells, such as lymphocytes and macrophages, and have been related to GCs resistance in diseases such as asthma, rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and acute lymphoblastic leukemia and chronic lymphocytic leukemia. Considering that GRβ can inhibit GRα activity, the modulation of GRα/GRβ expression ratios may be an interesting approach to regulate GC sensitivity. In addition, eight alternative translation initiation sites increase the repertory of GR proteins to almost 40 distinct isoforms of GR protein (Figure 1B).

At the cellular level, GC availability is also modulated by enzymes of the 11β-hydroxysteroid dehydrogenase (11β-HSD) family, mainly 11β-HSD1 and 11β-HSD2 which regulate the conversion of active cortisol into inactive cortisone. 11β-HSD1 favors the conversion of cortisol from cortisone, increasing local GC activity. In contrast, 11β-HSD2 catalyzes cortisol to cortisone, thereby reducing GC availability. Thus, the balance in the expression of these two enzymes in a given tissue or cell, regulates GC-mediated responses. In addition, some studies show that inflammatory cytokine signaling modulates the relative expression of 11β-HSD genes, favoring 11β-HSD1 and inhibiting 11β-HSD2, adding another level of regulation of GC activity.

Another important level for fine-tuning the cellular response to GCs in different environmental situations is the modulation of GR activity by posttranslational modifications (PTMs). These PTMs include phosphorylation, acetylation, ubiquitination, and sumoylation, which may accurately regulate GR activity in response to diverse external stimuli (Figure 1A). In particular, SUMO conjugation has been extensively described to modulate GR transcriptional activity. GR contains three consensus sumoylation sites. Two sumoylation sites located at the NTD have been demonstrated to be part of the synergy control (SC) motif sequence. The SC motifs consist of short regulatory sequences which are important for inhibiting the synergistic transactivation. SUMO conjugation to the two NTD sumoylation sites is responsible for the functional effect of the SC motifs and thereby they inhibit GR activity (Figure 1A). It has also been demonstrated that in the presence of the sumoylation enhancer, RSUME, a SUMO peptide is conjugated to the third sumoylation site located in the LBD of the GR. Sumoylation in the LBD may be important for inducing GR-mediated transcriptional regulation during stress adaptation (Figure 1A). A genome-wide analysis of GR sumoylation impact on gene expression, showed that genes differentially regulated by this PTM are mostly related to proliferation and apoptosis pathways and also strongly suggests that sumoylation can regulate genome-wide chromatin occupancy of the GR. Also, GR SUMO conjugation is influenced by other PTMs such as phosphorylation in order to fine-tune GR transcriptional activity in a target gene-specific manner. Important coregulators of the GR are also modified by SUMO conjugation, such as Hsp90, GRIP1, and also FKBP51, further regulating GR activity. Therefore, PTMs that impact on the GR but also on key molecules that fine-tune its activity, helps to understand the complexity of GR-mediated regulation of its target gene expression.

GCs Anti-Inflammatory Actions

The GR forms complex with chaperone molecules, such as Hsp90 and 70, and immunophilins, such as FKBP51, FKBP52, Cyp44, and PP5. FKBP51 binds to the unbound GR and reduces GR activity mainly by reducing GR hormone binding and its nuclear translocation. Therefore, FKBP51 is considered as an inhibitor of GR transcriptional activity. Upon ligand binding, the GR exchanges FKBP51 for FKBP52, which is able to interact with the dynein motor protein, facilitating GR translocation to the nucleus. Interestingly, FKBP51 overexpression has been associated with GC resistance in autoimmune diseases. FKBP51 expression was found to be enhanced in sputum samples from patients with chronic obstructive pulmonary disease. Moreover, in a genome-wide profiling focused on the identification of epithelial gene markers of asthmatic patients and response to corticosteroids, GC treatment was found to induce FKBP51 expression, which in turn was associated with a poor response to corticosteroids, suggesting a role of FKBP51 in GC resistance. Also, enhanced expression of FKBP51 has been found in bone marrow cells in patients with rheumatoid arthritis. Evidence also suggests that FKBP51 modulates NFĸB-dependent gene expression, with possible implications for various inflammatory and immune pathways. Considering that GR is a key modulator of immune and inflammatory responses, FKBP51 dysregulation may provide the basis for a role of FKBP51 in these processes. Moreover, FKBP51 has recently been shown to be a target of SUMO conjugation and that sumoylation of FKBP51 is necessary for its association to Hsp90 and modulates FKBP51-mediated inhibition of GR activity in neuronal cells. In the brain, FKBP51 has been shown to be important for the development of psychiatric diseases and the response to antidepressant treatment, suggesting that regulation of FKBP51 activity might be an interesting approach for modulating GR outcome in the stress response and also in the inflammatory context.

Once in the nucleus, the activated GR can regulate gene expression by different mechanisms known as genomic effects (Figure 1C). The genomic mechanism involves changes in the levels of specific genes: binding of GR to GREs in the promoters of its target genes and activation of transcription (transactivation); DNA binding of the GR with other TFs to “composite” elements which contain a GRE and an overlapping response element of another TF (binding can lead to gene activation or repression); or binding of the GR to a TF (e.g., NFĸB; or AP1) by means of a “tethering” mechanism without contacting DNA, to influence the activity of the TF (this mechanism is considered to be the prevailing mechanism for transrepression). Furthermore, GR-mediated transcriptional repression can be exerted via GR binding to a negative GRE (nGRE). Binding to these nGRE prevent receptor dimerization through a strong negative cooperativity and alters the conformation of GR residues that are critical for transcriptional activation so that negative regulation is accomplished. A growing body of evidence shows that GC can also mediate non-genomic actions that do not require protein synthesis and are implicated in rapid cellular responses. For example, in the cytoplasm the activated GR can acutely interact with signaling pathways, such as PI3K, JNK, 14-3-3 proteins, and components of the T cell receptor signaling complex, modulating pro-inflammatory gene expression. In thymocytes, the activated GR can translocate to mitochondria and induce a rapid apoptotic response. In addition, membrane-bound GR on monocytes was reported to mediate non-genomic effects. On the other hand, binding of GCs to GR can modify the recruitment of different factors such as the multiprotein chaperone complex that participate in many signaling pathways, modifying secondary signaling cascades and, therefore, may further regulate the immune response. GCs may also exert anti-inflammatory responses by direct negative interaction with components of the MAPK pathway, such as ERK, c-Jun NH2-terminal kinases (JNK), and p38 isoforms (p38) regulating their activity. Further studies are required to clarify the implications of non-genomic GC-mediated activity in the immune and inflammatory context.

It has been shown that several of the undesirable metabolic side effects associated with chronic GC treatment are mediated via transactivation. However the anti-inflammatory effects of GCs are mainly mediated via the transrepression elicited by a monomeric GR with the activity of TFs, such as NFĸB and AP1. These TFs are involved in the activation of pro-inflammatory and immunoregulatory genes, such as inflammatory cytokines, cytokine receptors, adhesion molecules, and chemotactic proteins that play a key role for the coordination of the inflammatory response. The first example of the transrepressive mechanism was the inhibitory interaction described between GR and AP1, which results in the inhibition of IL2 expression. NFĸB is present in almost all immune cells and regulates the expression of inflammatory cytokines. Thus, inhibition of NFĸB activity is an important feature for GR-mediated anti-inflammatory activity. It also inhibits NFAT-dependent IL2 transcription. The main mechanism of the GR action over these TFs is via transrepression: the activated GR acts by binding proximal to the NFĸB or AP1-binding site and interacts with these TFs inhibiting gene expression. The transrepression mechanism is not restricted to these TFs, but has expanded including among others, CREB, STAT, and T-bet.

Alterations in chromatin structure have been reported to be important for regulating GC actions. The GR can differentially interact with proteins that have histone acetyltransferase (HAT) activity, but also with histone deacetylases and kinases that can influence the chromatin environment modifying chromatin accessibility and further regulating immune and inflammatory gene expression. In addition, chromatin accessibility has been reported to pre-determine GR binding patterns and, therefore, is critical for cell-specific outcome, providing new molecular basis for the tissue selectivity. By all these different mechanisms, GCs regulate important functions, not only in the periphery but also in the brain.

Synthetic analogs of GC are often employed in the clinic in the therapy of allergic, inflammatory, and autoimmune disorders. It is generally accepted that GR-mediated transrepression holds the beneficial anti-inflammatory action, whereas their side effects are due mainly to the direct binding of GR to GREs as depicted before. However, transactivation is also necessary for the induction of several anti-inflammatory genes, such as MAP kinase phosphatase 1, glucocorticoid-induced leucine zipper, and inhibitor kappa B-alpha (IĸBα). Therefore, the ideal GC analogs should be those that have high repressive activity against inflammatory mediators, but low transactivation activity, causing minimal side effects. Several steroidal and nonsteroidal ligands have been reported to have this dissociated function between transactivation and transrepressive mechanisms. These compounds were shown to repress the activity of key inflammatory and immune TFs in vivo. However, GCs can induce gene expression not only by binding to GRE, but also in combination with other TFs and also by binding to promoter regions in a mechanism that does not involve GR dimerization or DNA interaction; therefore, unexpected secondary side effects might appear.

GCs may exert acute anti-inflammatory effects through the release of annexin-A1 (ANXA1). Originally, this protein was suggested to have anti-inflammatory actions because it was described to inhibit phospholipase A2. However, ANXA1 has been reported to regulate different cellular processes, such as migration, growth, differentiation, apoptosis, membrane fusion during exocytosis, lipid metabolism, and cytokine expression. Importantly, in the HPA axis, ANXA1 has been reported to play a critical role in the negative feedback exerted by GCs, therefore, affecting hypothalamic-releasing hormones secretion possibly via non-genomic mechanisms.

GCs Activity on Peripheral Immune Cells

GCs mediate immunosuppressive functions by acting on almost all types of immune cells (Figure 2). GCs can regulate the phenotype, survival, and functions of monocytes and macrophages which have crucial roles in tissue homeostasis and innate immunity. GCs exhibit anti-apoptotic effects promoting the survival of anti-inflammatory macrophages. The intrinsic molecular mechanism involves a prolonged induction of the extracellular signal-regulated kinase/MAPK (ERK/MAPK) pathway resulting in inhibition of caspase activities and expression of anti-apoptotic genes. GCs can also improve the phagocytic activity of these cells and stimulate the clearance of harmful elements, such as neutrophil clearance. GCs also suppress immunostimulatory functions of these cells and inhibit the release of various pro-inflammatory mediators, such as cytokines, chemokines, and reactive oxygen through different mechanisms. Functional clustering of GC-regulated genes by human anti-inflammatory macrophages by microarray technology indicated induction of phagocytosis and motility as well as repression of adhesion, apoptosis, and oxidative burst.

GCs can regulate the maturation, survival, and migration toward the lymph nodes and motility of dendritic cells (DCs), and also inhibit their immunogenic functions (Figure 2). GCs were shown to reduce the ability of DCs to stimulate T cells by inhibiting the upregulation of co-stimulatory molecules and cytokines, such as IL6, IL12, and TNFα and by inducing the tolerance-inducing transcription factor GILZ. The distinct actions exerted by GCs in immature and mature DCs are due to differential expression of GR translational isoforms.

GCs are important modulators of neutrophilia (Figure 2). Leukocyte extravasation is the movement of leukocytes out of the circulation and toward the site of tissue damage or infection. Rolling, adhesion, activation, and transmigration are necessary to arrive to the damaged tissue. GCs can modulate each of these steps. Rolling and adhesion is mediated by the interaction of the leukocyte integrins with the endothelial counterparts, which are inhibited by GCs. Also, GCs increase the number of circulating neutrophils in the blood stream by favoring their egress from the bone marrow and also inhibiting their migration to inflammatory sites by hindering the expression of adhesion molecules.

GCs exert distinct immunomodulatory actions on T cells (Figure 2). GCs decrease the number of circulating T cells by favoring their migration back to the bone marrow and secondary lymphoid tissues or through the induction of chemokine receptors, adhesion molecules, and matrix metalloproteinases. The steroid hormone also favors T cells apoptosis. GC-induced apoptosis of T cells requires the dimerization of the GR and is mediated via the induction of Puma and Bim expression. The relative expression of distinct GR isoforms increases the susceptibility of T cells to GC-induced cell death. Helper T (Th) cells are important players of the adaptive immunity. Upon antigen stimulation, naive Th cells can differentiate into different subsets: Th1, Th2, Th17, or regulatory T (Tregs) cells among others, each with specific effector functions. Th1 cells express the lineage-specific TF T-bet and STAT4 and release pro-inflammatory cytokines, such as IFNγ and IL2. Th1 cells help in the activation of effector T cells, natural killer (NK) cells, and macrophages at the site of infection, promote effective immune responses against intracellular pathogens and are also implicated in autoimmune pathologies. Th2 lymphocytes selectively express the TF GATA3 and are characterized by the expression of IL5, IL4, IL10, and IL13 and are important for the proper eradication of extracellular pathogens. Also, Th2 cells activate B cells to produce antibodies and play a triggering role in the activation/recruitment of eosinophils and mast cells in allergic responses. IL17-producing Th17 cells selectively express RORγt and also RORα. Th17 cells play an important role in autoimmune diseases and in host defense against infection. Treg cells mainly express the TF Foxp3 and inhibit effector T-cell differentiation and proliferation and suppress autoimmune and allergic responses. GCs inhibit the expression of many T cell cytokines and can produce a shift from Th1-mediated cellular immunity to mediating humoral Th2 responses at physiological doses or chronic treatment. Upon acute treatment with GCs, they inhibit the synthesis of Th1 cytokines like IL2 and IFNγ and reduce STAT4 activity and also reduce Th2 cytokines expression. The molecular mechanism by which GCs inhibit Th1 responses involves the reduction of T-bet transcriptional activity by the inhibitory interaction between GR and T-bet that results in diminished binding of T-bet to DNA (Figure 2). Also GCs where shown to reduce mRNA and protein levels of T-bet. The activity of the Th2-specific TF GATA3 is also suppressed by GCs via two main mechanisms: first by GR-mediated inhibition of GATA3 translocation into the nucleus and second by the inhibition of GATA3 phosphorylation by GC-induced MKP1 expression (Figure 2). Furthermore, STAT6 activity also involved in Th2 differentiation is inhibited by GCs. How GCs modulate Th17-mediated responses has not been extensively studied, and the importance of Th17 modulation by GCs for the suppression of allergic or autoimmune diseases remains unclear. In rheumatoid arthritis, GC treatment diminished IL17 levels. In addition, in rat lymphocytes methylprednisolone inhibited IL17 expression due to the inhibition of RORγt expression (Figure 2). However, several studies strongly suggest that GC resistance is associated with a pathogenic inflammatory Th17 phenotype that is refractory to GCs. Recently, a gene-expression profiling to characterize the steroid-resistant phenotype showed that Th17 cells have restricted genome-wide responses to GCs and that they are refractory to GC inhibition at this level. In addition, Th17 cells were sensitive to suppression with the calcineurin inhibitor, cyclosporine A, suggesting that the clinical efficacy of cyclosporine A in the treatment of steroid resistance may be due to its selective inhibition of Th17 cells. Another interesting study has shown that Th17 cells are insensitive to GC-induced apoptosis and had high levels of BCL-2, knockdown of which sensitized Th17 cells to GC-induced cell death. Also, lung Th17 development in the murine severe asthma model was enhanced by GCs, supporting a role of Th17 cells in GC-refractory inflammatory conditions such as asthma.

In contrast to the inhibitory effect of GCs on pro-inflammatory effector T cells, it has been shown that Treg cells, which are key suppressors of T cell-dependent immune responses, are enhanced upon dexamethasone treatment by being more resistant to GC-induced cell death (Figure 2). Also, GCs where shown to amplify IL2-dependent expansion of Treg cells and to enhance their capacity to reduce experimental autoimmune encephalomyelitis (EAE) in mice. In addition, GCs increase the percentage of Treg cells that express Foxp3 in patients with multiple sclerosis. In vivo, T cell-specific targeted GR deletion in pregnant animals undergoing EAE, resulted in a reduction of Treg population and a loss of pregnancy-induced protection, suggesting that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. However, others have found that GC treatment suppresses the expression of Foxp3 Tregs in an EAE model and also in lungs of allergic mice.

In addition to their well-studied anti-inflammatory and immunosuppressive activity, an increasing body of evidence has revealed situations in which GCs have the opposite effect. This has been shown to depend on the dose, timing, duration of exposure, and cell population or tissue analyzed. The paradoxical pro-inflammatory role of GCs is mostly evident in the brain, where accumulating evidence show that GCs elicit different immune responses depending on the affected brain regions.

GCs Actions in the Brain

There is a significant body of evidence indicating that GCs can suppress the innate immunity in the brain after a peripheral or cerebral challenge. In this way, in adrenalectomized mice, there is an induction in the levels of pro-inflammatory cytokines in the brain following LPS injection. Studies also demonstrated that GCs inhibit the release of pro-inflammatory mediators in microglial cells treated with LPS. Experiments performed in vivo support these findings by revealing that dexamethasone causes a strong reduction in LPS induction of NFĸB expression in the brain. In addition, COX inhibitors were demonstrated to increase the expression of pro-inflammatory genes in the brain during systemic inflammation by reducing the activation of the HPA axis and the release of GCs. This same effect took place when the GR antagonist RU486 was administrated. Also, systemic inflammation, through the increase in circulating GCs, has been reported to have the ability to prevent the cerebral innate immune response induced by intraparenchymal endotoxin injection. Mice treated with the GR antagonist RU486 before intracerebral LPS administration showed an increase in the pro-inflammatory response, which in turn induced neuronal death. These findings suggest that GCs are important for protecting the brain during innate immunity. Interestingly, when mice lacking GR in microglia were challenged with an intracerebral administration of LPS, the activation of the toll-like receptor 4 signaling pathway induced cellular lesion, and also neuronal and axonal damage. In addition, microglial cell cultures have reduced motility and increased amoeboid morphology in the absence of GR expression. This study strongly suggests that microglial GR is the principal mediator preventing neuronal degeneration triggered by LPS and that it also contributes to the protection of other cell types, having an important role in promoting neuronal survival.

The majority of GC pro-inflammatory activity has been described in animal models of acute or chronic stress which occurred previous to peripheral or cerebral immune challenges. For instance, acute stressors were reported to induce the expression of pro-inflammatory cytokines in specific brain regions, such as the hippocampus, following LPS peripheral challenge. GCs were also found to upregulate microglial activation markers including the toll-like receptor 2 pro-inflammatory pathway (Figure 3A). It was also shown that chronic unpredictable stress was able to potentiate LPS-mediated activation of NFĸB activity in the frontal cortex and hippocampus via GC production. Also, chronically stressed animals that were injected with LPS in the prefrontal cortex or the hippocampus, exhibited microglia activation, an increase in pro-inflammatory mediators and loss of astroglia and neurons. These effects were reduced with RU486 administration. The prefrontal cortex is important in many brain functions and is a target for neurodegenerative diseases. It has been reported that in this brain region, TNFα expression and activation of MAPK signaling pathway is upregulated by chronic stress after intracortical LPS injection in a GR-dependent manner suggesting a synergistic effect between inflammation and stress. This fact could ultimately explain the relationship described between stress and some neurodegenerative pathologies. In order to investigate if stress-induced GCs is responsible for the response of brain immune cells to pro-inflammatory stimuli, animals were acutely stressed and 24 h later hippocampal microglia were challenged with LPS ex vivo. Treatment in vivo with RU486 and adrenalectomized inhibited the microglial pro-inflammatory response, indicating that stress-induced GCs are able to sensitize the microglial pro-inflammatory function. Therefore, stress may act “priming” central innate immunity to a subsequent immune challenge by making the neuroimmune context more responsive to inflammation, also favoring GC insensitivity or reducing the HPA response. In addition, acute restraint stress, inescapable tail shock and other stressors induce many inflammatory mediators, reduce immunoregulatory proteins and trigger microglia activation and proliferation. In addition, GCs have been reported to increase the expression of the purinergic receptor P2Y2R (Figure 3B) which promotes the secretion of inflammatory mediators in response to ATP. Recent data also indicate that GCs induce the expression of NLRP3 (NLRP3: nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) in macrophages, which is a critical component of the inflammasome (Figure 3B). The GC-dependent induction of NLRP3 sensitizes the cells to extracellular ATP and significantly enhances the ATP-mediated release of pro-inflammatory molecules. This effect was specific for GCs and dependent on the GR and suggests that GCs sensitize the initial inflammatory response in the context of acute cellular damage or death. In addition, GCs and TNFα were shown to coregulate immune gene expression when combined. These results suggest that the final outcome of GCs pro- or anti-inflammatory activity depends on the activation state and signaling context. GCs are also able to modulate the inflammatory response to LPS in different ways according to the brain region. For example, GR activation during chronic stress increases LPS-induced NFκB activation and TNFα, IL1β, and iNOS expression in the hippocampus and frontal cortex, but exhibits contrary effects in the hypothalamus. It is important to keep in mind that a pro-inflammatory context does not necessarily mean that damage will take place. Timing is a key parameter that will determine the final outcome of the inflammatory response. While exaggerated inflammation can favor neuronal dysfunction and cell death, pro-inflammatory mediators may at first induce the removal of the pathogen, the recruitment of immune cells and initiate tissue remodeling in order to appropriately cope with the pathogen and therefore, restoring homeostasis.

Conclusion

GCs are widely used in the clinic to control not only peripheral, but also CNS inflammatory response. However, the prolonged administration of this steroid hormone is often ineffective and can even worsen the outcome of the disease. Considering the known undesirable metabolic side effect, the induction of pro-inflammatory responses and the existence of GC resistance, GCs should be used carefully. Future research should be focused not only in understanding the molecular basis of GCs side effects and resistance, but also in dissecting how GCs induce pro-inflammatory responses in order to avoid serious detrimental consequences, particularly in the brain. In the future, a combination of different therapeutic approaches may lead to a more effective treatment and may help to lower the doses or duration of GC treatment thus minimizing the risk of toxicity and drug resistance. Finally, taking into account inter-individual differences in patient responsiveness to GC treatment, where different molecular mechanisms might be implicated, future directions should be in support of a customized and personalized treatment to meet individual patient needs.

Author Contributions

AL: wrote, discussed, and corrected the manuscript. MB: discussed and corrected the manuscript. CS: discussed and corrected the manuscript, performed the figures. RG: discussed and corrected the manuscript, performed the figures. AS: corrected the manuscript. EA: discussed and corrected the manuscript.

Conflict of Interest Statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. The reviewer LD and handling Editor declared their shared affiliation.

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    Edwards CK III Yunger LM Lorence RM Dantzer R Kelley KW. The pituitary gland is required for protection against lethal effects of Salmonella typhimurium. Proc Natl Acad Sci U S A (1991 ) 88:2274–7.

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    Ramachandra RN Sehon AH Berczi I. Neuro-hormonal host defence in endotoxin shock. Brain Behav Immun (1992 ) 6:157–69.

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    Evans RM. The steroid and thyroid hormone receptor superfamily. Science (1988 ) 240:889–95.

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    Glass CK Rose DW Rosenfeld MG. Nuclear receptor coactivators. Curr Opin Cell Biol (1997 ) 9:222–32.

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    Bledsoe RK Montana VG Stanley TB Delves CJ Apolito CJ McKee DD Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell (2002 ) 110:93–105.

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    Cain DW Cidlowski JA. Specificity and sensitivity of glucocorticoid signaling in health and disease. Best Pract Res Clin Endocrinol Metab (2015 ) 29:545–56.

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    Oakley RH Cidlowski JA. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem (2011 ) 286:3177–84.

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    Busillo JM Azzam KM Cidlowski JA. Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome. J Biol Chem (2011 ) 286:38703–13.

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    Ligr M Li Y Logan SK Taneja S Melamed J Lepor H Mifepristone inhibits GRbeta coupled prostate cancer cell proliferation. J Urol (2012 ) 188:981–8.

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    Lewis-Tuffin LJ Jewell CM Bienstock RJ Collins JB Cidlowski JA. Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active. Mol Cell Biol (2007 ) 27:2266–82.

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    Oakley RH Jewell CM Yudt MR Bofetiado DM Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem (1999 ) 274:27857–66.

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    Sousa AR Lane SJ Cidlowski JA Staynov DZ Lee TH. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol (2000 ) 105:943–50.

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    Chikanza IC. Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid receptor beta isoform. Ann N Y Acad Sci (2002 ) 966:39–48.

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    Honda M Orii F Ayabe T Imai S Ashida T Obara T Expression of glucocorticoid receptor beta in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis. Gastroenterology (2000 ) 118:859–66.

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    Piotrowski P Burzynski M Lianeri M Mostowska M Wudarski M Chwalinska-Sadowska H Glucocorticoid receptor beta splice variant expression in patients with high and low activity of systemic lupus erythematosus. Folia Histochem Cytobiol (2007 ) 45:339–42.

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    Koga Y Matsuzaki A Suminoe A Hattori H Kanemitsu S Hara T. Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children. Pediatr Blood Cancer (2005 ) 45:121–7.

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    Shahidi H Vottero A Stratakis CA Taymans SE Karl M Longui CA Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia. Biochem Biophys Res Commun (1999 ) 254:559–65.

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    Lu NZ Collins JB Grissom SF Cidlowski JA. Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor. Mol Cell Biol (2007 ) 27:7143–60.

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    Cain DW Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol (2017 ) 17:233–47.

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    Cooper MS Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J Clin Endocrinol Metab (2009 ) 94:4645–54.

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    Stegk JP Ebert B Martin HJ Maser E. Expression profiles of human 11beta-hydroxysteroid dehydrogenases type 1 and type 2 in inflammatory bowel diseases. Mol Cell Endocrinol (2009 ) 301:104–8.

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    Zbánková S Bryndová J Leden P Kment M Svec A Pácha J. 11Beta-hydroxysteroid dehydrogenase 1 and 2 expression in colon from patients with ulcerative colitis. J Gastroenterol Hepatol (2007 ) 22:1019–23.

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    Liberman AC Antunica-Noguerol M Arzt E Modulation of the glucocorticoid receptor activity by post-translational modifications. Nucl Recept Res (2014 ) 1:1–15.

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    Golebiowski F Matic I Tatham MH Cole C Yin Y Nakamura A System-wide changes to SUMO modifications in response to heat shock. Sci Signal (2009 ) 2:ra24.

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    Holmstrom S Van Antwerp ME Iñiguez-Lluhi JA. Direct and distinguishable inhibitory roles for SUMO isoforms in the control of transcriptional synergy. Proc Natl Acad Sci U S A (2003 ) 100:15758–63.

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    Le Drean Y Mincheneau N Le Goff P Michel D. Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology (2002 ) 143:3482–9.

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    Tian S Poukka H Palvimo JJ Jänne OA. Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor. Biochem J (2002 ) 367:907–11.

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    Iñiguez-Lluhí JA Pearce D. A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy. Mol Cell Biol (2000 ) 20:6040–50.

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  54. 54.

    Carbia-Nagashima A Gerez J Perez-Castro C Paez-Pereda M Silberstein S Stalla GK RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell (2007 ) 131:309–23.

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  55. 55.

    Druker J Liberman AC Antunica-Noguerol M Gerez J Paez-Pereda M Rein T RSUME enhances glucocorticoid receptor SUMOylation and transcriptional activity. Mol Cell Biol (2013 ) 33:2116–27.

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  56. 56.

    Paakinaho V Kaikkonen S Makkonen H Benes V Palvimo JJ. SUMOylation regulates the chromatin occupancy and anti-proliferative gene programs of glucocorticoid receptor. Nucleic Acids Res (2014 ) 42:1575–92.

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    Davies L Karthikeyan N Lynch JT Sial EA Gkourtsa A Demonacos C Cross talk of signaling pathways in the regulation of the glucocorticoid receptor function. Mol Endocrinol (2008 ) 22:1331–44.

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    Antunica-Noguerol M Budziñski ML Druker J Gassen NC Sokn MC Senin S The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51. Cell Death Differ (2016 ) 23:1579–91.

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  59. 59.

    Kotaja N Karvonen U Jänne OA Palvimo JJ. The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. J Biol Chem (2002 ) 277:30283–8.

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  60. 60.

    Panse VG Hardeland U Werner T Kuster B Hurt E. A proteome-wide approach identifies sumoylated substrate proteins in yeast. J Biol Chem (2004 ) 279:41346–51.

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  61. 61.

    Pountney DL Raftery MJ Chegini F Blumbergs PC Gai WP. NSF, Unc-18-1, dynamin-1 and HSP90 are inclusion body components in neuronal intranuclear inclusion disease identified by anti-SUMO-1-immunocapture. Acta Neuropathol (2008 ) 116:603–14.

    Not in our library10.1007/s00401-008-0437-4

  62. 62.

    Zhou W Ryan JJ Zhou H. Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses. J Biol Chem (2004 ) 279:32262–8.

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  63. 63.

    Pratt WB Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) (2003 ) 228:111–33.

    Not in our library10.1177/153537020322800201

  64. 64.
    Differential impact of tetratricopeptide repeat proteins on the steroid hormone receptors. · 2010
    Not checked
  65. 65.

    Holownia A Mroz RM Kolodziejczyk A Chyczewska E Braszko JJ. Increased FKBP51 in induced sputum cells of chronic obstructive pulmonary disease patients after therapy. Eur J Med Res (2009 ) 14(Suppl 4):108–11.

    Not in our library10.1186/2047-783x-14-s4-108

  66. 66.

    Storer CL Dickey CA Galigniana MD Rein T Cox MB. FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab (2011 ) 22:481–90.

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    Woodruff PG Boushey HA Dolganov GM Barker CS Yang YH Donnelly S Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A (2007 ) 104:15858–63.

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    Matsushita R Hashimoto A Tomita T Yoshitawa H Tanaka S Endo H Enhanced expression of mRNA for FK506-binding protein 5 in bone marrow CD34 positive cells in patients with rheumatoid arthritis. Clin Exp Rheumatol (2010 ) 28:87–90.

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  69. 69.

    Baker RG Hayden MS Ghosh S NF-kappaB, inflammation, and metabolic disease. Cell Metab (2011 ) 13:11–22.

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  70. 70.

    Erlejman AG De Leo SA Mazaira GI Molinari AM Camisay MF Fontana V NF-kappaB transcriptional activity is modulated by FK506-binding proteins FKBP51 and FKBP52: a role for peptidyl-prolyl isomerase activity. J Biol Chem (2014 ) 289:26263–76.

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  71. 71.

    Hayden MS Ghosh S NF-kappaB in immunobiology. Cell Res (2011 ) 21:223–44.

    Not in our library10.1038/cr.2011.13

  72. 72.

    Nakamura N Shimaoka Y Tougan T Onda H Okuzaki D Zhao H Isolation and expression profiling of genes upregulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients. DNA Res (2006 ) 13:169–83.

    Not in our library10.1093/dnares/dsl006

  73. 73.

    Park J Kim M Na G Jeon I Kwon YK Kim JH Glucocorticoids modulate NF-kappaB-dependent gene expression by up-regulating FKBP51 expression in Newcastle disease virus-infected chickens. Mol Cell Endocrinol (2007 ) 278:7–17.

    Not in our library10.1016/j.mce.2007.08.002

  74. 74.

    Binder EB Salyakina D Lichtner P Wochnik GM Ising M Pütz B Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet (2004 ) 36:1319–25.

    Not in our library10.1038/ng1479

  75. 75.

    Zannas AS Wiechmann T Gassen NC Binder EB. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology (2016 ) 41:261–74.

    Not in our library10.1038/npp.2015.235

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    Zimmermann P Brückl T Nocon A Pfister H Binder EB Uhr M Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study. Am J Psychiatry (2011 ) 168:1107–16.

    Not in our library10.1176/appi.ajp.2011.10111577

  77. 77.

    De Bosscher K Haegeman G. Minireview: latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrinol (2009 ) 23:281–91.

    Not in our library10.1210/me.2008-0283

  78. 78.

    Desmet SJ De Bosscher K. Glucocorticoid receptors: finding the middle ground. J Clin Invest (2017 ) 127:1136–45.

    Not in our library10.1172/jci88886

  79. 79.

    Surjit M Ganti KP Mukherji A Ye T Hua G Metzger D Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell (2011 ) 145:224–41.

    Not in our library10.1016/j.cell.2011.03.027

  80. 80.

    Hudson WH Youn C Ortlund EA. The structural basis of direct glucocorticoid-mediated transrepression. Nat Struct Mol Biol (2013 ) 20:53–8.

    Not in our library10.1038/nsmb.2456

  81. 81.

    Löwenberg M Stahn C Hommes DW Buttgereit F. Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands. Steroids (2008 ) 73:1025–9.

    Not in our library10.1016/j.steroids.2007.12.002

  82. 82.

    Boldizsar F Talaber G Szabo M Bartis D Palinkas L Nemeth P Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells. Immunobiology (2010 ) 215:521–6.

    Not in our library10.1016/j.imbio.2009.10.003

  83. 83.

    Croxtall JD Choudhury Q Flower RJ. Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br J Pharmacol (2000 ) 130:289–98.

    Not in our library10.1038/sj.bjp.0703272

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    Ayroldi E Cannarile L Migliorati G Nocentini G Delfino DV Riccardi C. Mechanisms of the anti-inflammatory effects of glucocorticoids: genomic and nongenomic interference with MAPK signaling pathways. FASEB J (2012 ) 26:4805–20.

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    Scheinman RI Gualberto A Jewell CM Cidlowski JA Baldwin AS Jr. Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Mol Cell Biol (1995 ) 15:943–53.

    Not in our library10.1128/mcb.15.2.943

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    De Bosscher K Vanden Berghe W Haegeman G. The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev (2003 ) 24:488–522.

    Not in our library10.1210/er.2002-0006

  87. 87.

    De Bosscher K Vanden Berghe W Haegeman G. Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene (2006 ) 25:6868–86.

    Not in our library10.1038/sj.onc.1209935

  88. 88.

    Pascual G Glass CK. Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab (2006 ) 17:321–7.

    Not in our library10.1016/j.tem.2006.08.005

  89. 89.

    Jonat C Rahmsdorf HJ Park KK Cato AC Gebel S Ponta H Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell (1990 ) 62:1189–204.

    Not in our library10.1016/0092-8674(90)90395-u

  90. 90.

    Helmberg A Auphan N Caelles C Karin M. Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J (1995 ) 14:452–60.

    Not in our library10.1002/j.1460-2075.1995.tb07021.x

  91. 91.

    Auphan N DiDonato JA Rosette C Helmberg A Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science (1995 ) 270:286–90.

    Not in our library10.1126/science.270.5234.286

  92. 92.

    Vacca A Felli MP Farina AR Martinotti S Maroder M Screpanti I Glucocorticoid receptor-mediated suppression of the interleukin 2 gene expression through impairment of the cooperativity between nuclear factor of activated T cells and AP-1 enhancer elements. J Exp Med (1992 ) 175:637–46.

    Not in our library10.1084/jem.175.3.637

  93. 93.

    De Bosscher K Schmitz ML Vanden Berghe W Plaisance S Fiers W Haegeman G. Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci U S A (1997 ) 94:13504–9.

    Not in our library10.1073/pnas.94.25.13504

  94. 94.

    Liberman AC Refojo D Druker J Toscano M Rein T Holsboer F The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB J (2007 ) 21:1177–88.

    Not in our library10.1096/fj.06-7452com

  95. 95.

    John S Sabo PJ Johnson TA Sung MH Biddie SC Lightman SL Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell (2008 ) 29:611–24.

    Not in our library10.1016/j.molcel.2008.02.010

  96. 96.

    John S Sabo PJ Thurman RE Sung MH Biddie SC Johnson TA Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet (2011 ) 43:264–8.

    Not in our library10.1038/ng.759

  97. 97.

    De Bosscher K Beck IM Haegeman G Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: survival of the fittest regulator of the immune system? Brain Behav Immun (2010 ) 24:1035–42.

    Not in our library10.1016/j.bbi.2010.06.010

  98. 98.

    De Bosscher K Haegeman G Elewaut D Targeting inflammation using selective glucocorticoid receptor modulators. Curr Opin Pharmacol (2010 ) 10:497–504.

    Not in our library10.1016/j.coph.2010.04.007

  99. 99.

    Liberman AC Castro CN Antunica Noguerol MA Barcala Tabarrozzi AE Druker J Perone MJ Immunomodulation by glucocorticoids: from basic research to clinical implications. Curr Immunol Rev (2010 ) 6:371–80.

    Not in our library

  100. 100.

    Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol (2011 ) 163:29–43.

    Not in our library10.1111/j.1476-5381.2010.01199.x

  101. 101.

    Vandevyver S Dejager L Van Bogaert T Kleyman A Liu Y Tuckermann J Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. J Clin Invest (2012 ) 122:2130–40.

    Not in our library10.1172/jci60006

  102. 102.

    Ronchetti S Migliorati G Riccardi C. GILZ as a mediator of the anti-inflammatory effects of glucocorticoids. Front Endocrinol (2015 ) 6:170.

    Not in our library10.3389/fendo.2015.00170

  103. 103.

    De Bosscher K Van Craenenbroeck K Meijer OC Haegeman G. Selective transrepression versus transactivation mechanisms by glucocorticoid receptor modulators in stress and immune systems. Eur J Pharmacol (2008 ) 583:290–302.

    Not in our library10.1016/j.ejphar.2007.11.076

  104. 104.

    Belvisi MG Wicks SL Battram CH Bottoms SE Redford JE Woodman P Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity. J Immunol (2001 ) 166:1975–82.

    Not in our library10.4049/jimmunol.166.3.1975

  105. 105.

    De Bosscher K Beck IM Dejager L Bougarne N Gaigneaux A Chateauvieux S Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-kappaB and AP-1. Cell Mol Life Sci (2014 ) 71:143–63.

    Not in our library10.1007/s00018-013-1367-4

  106. 106.

    De Bosscher K Vanden Berghe W Beck IM Van Molle W Hennuyer N Hapgood J A fully dissociated compound of plant origin for inflammatory gene repression. Proc Natl Acad Sci U S A (2005 ) 102:15827–32.

    Not in our library10.1073/pnas.0505554102

  107. 107.

    Vayssière BM Dupont S Choquart A Petit F Garcia T Marchandeau C Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. Mol Endocrinol (1997 ) 11:1245–55.

    Not in our library10.1210/me.11.9.1245

  108. 108.
    Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance · 2016
    No notice
  109. 109.

    Errasfa M Russo-Marie F. A purified lipocortin shares the anti-inflammatory effect of glucocorticosteroids in vivo in mice. Br J Pharmacol (1989 ) 97:1051–8.

    Not in our library10.1111/j.1476-5381.1989.tb12561.x

  110. 110.

    Buckingham JC John CD Solito E Tierney T Flower RJ Christian H Annexin 1, glucocorticoids, and the neuroendocrine-immune interface. Ann N Y Acad Sci (2006 ) 1088:396–409.

    Not in our library10.1196/annals.1366.002

  111. 111.

    Barczyk K Ehrchen J Tenbrock K Ahlmann M Kneidl J Viemann D Glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3. Blood (2010 ) 116:446–55.

    Not in our library10.1182/blood-2009-10-247106

  112. 112.

    Fadok VA Bratton DL Konowal A Freed PW Westcott JY Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest (1998 ) 101:890–8.

    Not in our library10.1172/jci1112

  113. 113.

    Liu Y Cousin JM Hughes J Van Damme J Seckl JR Haslett C Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J Immunol (1999 ) 162:3639–46.

    Not in our library

  114. 114.

    McColl A Bournazos S Franz S Perretti M Morgan BP Haslett C Glucocorticoids induce protein S-dependent phagocytosis of apoptotic neutrophils by human macrophages. J Immunol (2009 ) 183:2167–75.

    Not in our library10.4049/jimmunol.0803503

  115. 115.

    Franchimont D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci (2004 ) 1024:124–37.

    Not in our library10.1196/annals.1321.009

  116. 116.

    Sauer J Castren M Hopfner U Holsboer F Stalla GK Arzt E. Inhibition of lipopolysaccharide-induced monocyte interleukin-1 receptor antagonist synthesis by cortisol: involvement of the mineralocorticoid receptor. J Clin Endocrinol Metab (1996 ) 81:73–9.

    Not in our library10.1210/jc.81.1.73

  117. 117.

    Ehrchen J Steinmüller L Barczyk K Tenbrock K Nacken W Eisenacher M Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood (2007 ) 109:1265–74.

    Not in our library10.1182/blood-2006-02-001115

  118. 118.

    Vallelian F Schaer CA Kaempfer T Gehrig P Duerst E Schoedon G Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity. Blood (2010 ) 116:5347–56.

    Not in our library10.1182/blood-2010-04-277319

  119. 119.

    Ayroldi E Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J (2009 ) 23:3649–58.

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    Cronstein BN Kimmel SC Levin RI Martiniuk F Weissmann G. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A (1992 ) 89:9991–5.

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    Reichardt HM Kaestner KH Tuckermann J Kretz O Wessely O Bock R DNA binding of the glucocorticoid receptor is not essential for survival. Cell (1998 ) 93:531–41.

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    Bouillet P Metcalf D Huang DC Tarlinton DM Kay TW Köntgen F Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science (1999 ) 286:1735–8.

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    Ramírez F Fowell DJ Puklavec M Simmonds S Mason D. Glucocorticoids promote a TH2 cytokine response by CD4+ T cells in vitro. J Immunol (1996 ) 156:2406–12.

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    Franchimont D Galon J Gadina M Visconti R Zhou Y Aringer M Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes. J Immunol (2000 ) 164:1768–74.

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    Barnes PJ Th2 cytokines and asthma: an introduction. Respir Res (2001 ) 2:64–5.

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    Liberman AC Druker J Refojo D Holsboer F Arzt E. Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells. FASEB J (2009 ) 23:1558–71.

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    Maneechotesuwan K Yao X Ito K Jazrawi E Usmani OS Adcock IM Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med (2009 ) 6:e1000076.

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    Biola A Andréau K David M Sturm M Haake M Bertoglio J The glucocorticoid receptor and STAT6 physically and functionally interact in T-lymphocytes. FEBS Lett (2000 ) 487:229–33.

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    Banuelos J Cao Y Shin SC Lu NZ. Immunopathology alters Th17 cell glucocorticoid sensitivity. Allergy (2017 ) 72:331–41.

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    Ziolkowska M Koc A Luszczykiewicz G Ksiezopolska-Pietrzak K Klimczak E Chwalinska-Sadowska H High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol (2000 ) 164:2832–8.

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    Momcilović M Miljković Z Popadić D Marković M Savić E Ramić Z Methylprednisolone inhibits interleukin-17 and interferon-gamma expression by both naive and primed T cells. BMC Immunol (2008 ) 9:47.

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    Ramesh R Kozhaya L McKevitt K Djuretic IM Carlson TJ Quintero MA Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med (2014 ) 211:89–104.

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    Schewitz-Bowers LP Lait PJ Copland DA Chen P Wu W Dhanda AD Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A. Proc Natl Acad Sci U S A (2015 ) 112:4080–5.

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    Banuelos J Shin S Cao Y Bochner BS Morales-Nebreda L Budinger GR BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis. Allergy (2016 ) 71:640–50.

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    Zhao J Lloyd CM Noble A. Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol (2013 ) 6:335–46.

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    Chen X Murakami T Oppenheim JJ Howard OMZ. Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death. Eur J Immunol (2004 ) 34:859–69.

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    Chen X Oppenheim JJ Winkler-Pickett RT Ortaldo JR Howard OM. Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3(+)CD4(+)CD25(+) T regulatory cells in vivo and enhances their capacity to suppress EAE. Eur J Immunol (2006 ) 36:2139–49.

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    Braitch M Harikrishnan S Robins RA Nichols C Fahey AJ Showe L Glucocorticoids increase CD4CD25 cell percentage and Foxp3 expression in patients with multiple sclerosis. Acta Neurol Scand (2009 ) 119:239–45.

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    Engler JB Kursawe N Solano ME Patas K Wehrmann S Heckmann N Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc Natl Acad Sci U S A (2017 ) 114:E181–90.

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    Wüst S van den Brandt J Tischner D Kleiman A Tuckermann JP Gold R Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis. J Immunol (2008 ) 180:8434–43.

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    Olsen PC Kitoko JZ Ferreira TP de-Azevedo CT Arantes AC Martins MA. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice. Eur J Pharmacol (2015 ) 747:52–8.

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    Sorrells SF Caso JR Munhoz CD Sapolsky RM. The stressed CNS: when glucocorticoids aggravate inflammation. Neuron (2009 ) 64:33–9.

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    Butler LD Layman NK Riedl PE Cain RL Shellhaas J Evans GF Neuroendocrine regulation of in vivo cytokine production and effects: I. In vivo regulatory networks involving the neuroendocrine system, interleukin-1 and tumor necrosis factor-alpha. J Neuroimmunol (1989 ) 24:143–53.

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    Goujon E Parnet P Cremona S Dantzer R. Endogenous glucocorticoids down regulate central effects of interleukin-1 beta on body temperature and behaviour in mice. Brain Res (1995 ) 702:173–80.

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    Goujon E Parnet P Layé S Combe C Dantzer R. Adrenalectomy enhances pro-inflammatory cytokines gene expression, in the spleen, pituitary and brain of mice in response to lipopolysaccharide. Brain Res Mol Brain Res (1996 ) 36:53–62.

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    Masferrer JL Seibert K Zweifel B Needleman P. Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc Natl Acad Sci U S A (1992 ) 89:3917–21.

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    Drew PD Chavis JA. Inhibition of microglial cell activation by cortisol. Brain Res Bull (2000 ) 52:391–6.

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    Tanaka J Fujita H Matsuda S Toku K Sakanaka M Maeda N. Glucocorticoid- and mineralocorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids. Glia (1997 ) 20:23–37.

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    Glezer I Munhoz CD Kawamoto EM Marcourakis T Avellar MC Scavone C. MK-801 and 7-Ni attenuate the activation of brain NF-kappa B induced by LPS. Neuropharmacology (2003 ) 45:1120–9.

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    Blais V Turrin NP Rivest S. Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli. J Neurochem (2005 ) 95:1563–74.

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    Blais V Zhang J Rivest S. In altering the release of glucocorticoids, ketorolac exacerbates the effects of systemic immune stimuli on expression of proinflammatory genes in the brain. Endocrinology (2002 ) 143:4820–7.

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    Nadeau S Rivest S. Endotoxemia prevents the cerebral inflammatory wave induced by intraparenchymal lipopolysaccharide injection: role of glucocorticoids and CD14. J Immunol (2002 ) 169:3370–81.

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    Nadeau S Rivest S. Glucocorticoids play a fundamental role in protecting the brain during innate immune response. J Neurosci (2003 ) 23:5536–44.

    Not in our library10.1523/jneurosci.23-13-05536.2003

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    Soulet D Rivest S. Bone-marrow-derived microglia: myth or reality? Curr Opin Pharmacol (2008 ) 8:508–18.

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    Carrillo-de Sauvage MÁ Maatouk L Arnoux I Pasco M Sanz Diez A Delahaye M Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation. Cell Death Differ (2013 ) 20:1546–57.

    Not in our library10.1038/cdd.2013.108

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    Frank MG Miguel ZD Watkins LR Maier SF. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun (2010 ) 24:19–30.

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    Johnson JD O’Connor KA Deak T Stark M Watkins LR Maier SF. Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav Immun (2002 ) 16:461–76.

    Not in our library10.1006/brbi.2001.0638

  180. 180.

    Johnson JD O’Connor KA Hansen MK Watkins LR Maier SF. Effects of prior stress on LPS-induced cytokine and sickness responses. Am J Physiol Regul Integr Comp Physiol (2003 ) 284:R422–32.

    Not in our library10.1152/ajpregu.00230.2002

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    Hermoso MA Matsuguchi T Smoak K Cidlowski JA. Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Mol Cell Biol (2004 ) 24:4743–56.

    Not in our library10.1128/mcb.24.11.4743-4756.2004

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    Munhoz CD Lepsch LB Kawamoto EM Malta MB Lima Lde S Avellar MC Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci (2006 ) 26:3813–20.

    Not in our library10.1523/jneurosci.4398-05.2006

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    de Pablos RM Villarán RF Argüelles S Herrera AJ Venero JL Ayala A Stress increases vulnerability to inflammation in the rat prefrontal cortex. J Neurosci (2006 ) 26:5709–19.

    Not in our library10.1523/jneurosci.0802-06.2006

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    Espinosa-Oliva AM de Pablos RM Villarán RF Argüelles S Venero JL Machado A Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus. Neurobiol Aging (2011 ) 32:85–102.

    Not in our library10.1016/j.neurobiolaging.2009.01.012

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    Frank MG Thompson BM Watkins LR Maier SF. Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses. Brain Behav Immun (2012 ) 26:337–45.

    Not in our library10.1016/j.bbi.2011.10.005

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    Frank MG Watkins LR Maier SF. Stress- and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse. Brain Behav Immun (2011 ) 25(Suppl 1):S21–8.

    Not in our library10.1016/j.bbi.2011.01.005

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    Frank MG Watkins LR Maier SF. Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger. Brain Behav Immun (2013 ) 33:1–6.

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    Blandino P Jr Barnum CJ Solomon LG Larish Y Lankow BS Deak T. Gene expression changes in the hypothalamus provide evidence for regionally-selective changes in IL-1 and microglial markers after acute stress. Brain Behav Immun (2009 ) 23:958–68.

    Not in our library10.1016/j.bbi.2009.04.013

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    Frank MG Baratta MV Sprunger DB Watkins LR Maier SF. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun (2007 ) 21:47–59.

    Not in our library10.1016/j.bbi.2006.03.005

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    García-Bueno B Madrigal JL Pérez-Nievas BG Leza JC. Stress mediators regulate brain prostaglandin synthesis and peroxisome proliferator-activated receptor-gamma activation after stress in rats. Endocrinology (2008 ) 149:1969–78.

    Not in our library10.1210/en.2007-0482

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    Madrigal JL Hurtado O Moro MA Lizasoain I Lorenzo P Castrillo A The increase in TNF-alpha levels is implicated in NF-kappaB activation and inducible nitric oxide synthase expression in brain cortex after immobilization stress. Neuropsychopharmacology (2002 ) 26:155–63.

    Not in our library10.1016/s0893-133x(01)00292-5

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    Madrigal JL Moro MA Lizasoain I Lorenzo P Fernández AP Rodrigo J Induction of cyclooxygenase-2 accounts for restraint stress-induced oxidative status in rat brain. Neuropsychopharmacology (2003 ) 28:1579–88.

    Not in our library10.1038/sj.npp.1300187

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    O’Connor KA Johnson JD Hammack SE Brooks LM Spencer RL Watkins LR Inescapable shock induces resistance to the effects of dexamethasone. Psychoneuroendocrinology (2003 ) 28:481–500.

    Not in our library10.1016/s0306-4530(02)00035-5

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    Ding Y Gao ZG Jacobson KA Suffredini AF. Dexamethasone enhances ATP-induced inflammatory responses in endothelial cells. J Pharmacol Exp Ther (2010 ) 335:693–702.

    Not in our library10.1124/jpet.110.171975

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    Lannan EA Galliher-Beckley AJ Scoltock AB Cidlowski JA Proinflammatory actions of glucocorticoids: glucocorticoids and TNFalpha coregulate gene expression in vitro and in vivo. Endocrinology (2012 ) 153:3701–12.

    Not in our library10.1210/en.2012-1020

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    De Bosscher K. Selective glucocorticoid receptor modulators. J Steroid Biochem Mol Biol (2010 ) 120:96–104.

    Not in our library10.1016/j.jsbmb.2010.02.027

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