Limits...
Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses.

Xavier AM, Anunciato AK, Rosenstock TR, Glezer I - Front Endocrinol (Lausanne) (2016)

Bottom Line: GC's effects on inflammation are generally mediated through GC receptors (GRs).In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling.Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo , Brazil.

ABSTRACT
Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC's effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.

No MeSH data available.


Related in: MedlinePlus

Global scheme of glucocorticoid signaling and transcriptional mechanism during inflammation. 1. Hypothalamus–pituitary–adrenal (HPA) signaling cascade upon stressors. CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotropic hormone; GCs, glucocorticoids. 2. The endogenous/synthetic GCs bind to glucocorticoid receptor (GR) and can act in two ways: non-genomic effects in cytoplasm or translocation into the nucleus, resulting in the modulation of the transcriptional responses (for example, the transactivation of anti-inflammatory genes). Alternatively, selective glucocorticoid receptor agonists (SEGRAs) can act majorly through tethering mechanism. 3. In the context of an inflammatory scenario, cytokines, DAMPS, and PAMPs bind to their respective receptors and activate pro-inflammatory transcription factors (TFs). These TFs translocate to the nucleus and increases the activity at pro-inflammatory genes promoters by GC–GR complex (composite sites, tethering, or compete for DNA-binding sites – not shown). 4. The four main transcriptional mechanisms involved in the inflammatory response: sGRE, nGRE, binding to composite sites and tethering. In the first two modes (sGRE and nGRE), the GC–GR complex modulates the transcription in a GRE-dependent manner activating or repressing genes, if accessible. In the last two modes (composite site and tethering), the GC–GR complex is recruited to GRE sites modulating gene expression in conjunction with TFs (composite site) or interacting directly with TFs (tethering) or coactivators (not shown). Please refer to main text for more details.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835445&req=5

Figure 1: Global scheme of glucocorticoid signaling and transcriptional mechanism during inflammation. 1. Hypothalamus–pituitary–adrenal (HPA) signaling cascade upon stressors. CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotropic hormone; GCs, glucocorticoids. 2. The endogenous/synthetic GCs bind to glucocorticoid receptor (GR) and can act in two ways: non-genomic effects in cytoplasm or translocation into the nucleus, resulting in the modulation of the transcriptional responses (for example, the transactivation of anti-inflammatory genes). Alternatively, selective glucocorticoid receptor agonists (SEGRAs) can act majorly through tethering mechanism. 3. In the context of an inflammatory scenario, cytokines, DAMPS, and PAMPs bind to their respective receptors and activate pro-inflammatory transcription factors (TFs). These TFs translocate to the nucleus and increases the activity at pro-inflammatory genes promoters by GC–GR complex (composite sites, tethering, or compete for DNA-binding sites – not shown). 4. The four main transcriptional mechanisms involved in the inflammatory response: sGRE, nGRE, binding to composite sites and tethering. In the first two modes (sGRE and nGRE), the GC–GR complex modulates the transcription in a GRE-dependent manner activating or repressing genes, if accessible. In the last two modes (composite site and tethering), the GC–GR complex is recruited to GRE sites modulating gene expression in conjunction with TFs (composite site) or interacting directly with TFs (tethering) or coactivators (not shown). Please refer to main text for more details.

Mentions: An inflammatory reaction relies on both fast triggering and tight control over intensity. Failure on fine-tuning immune cells activation and pro-inflammatory signaling can lead to unnecessary expended energy and tissue damage. Endogenous glucocorticoids (GCs), as cortisol in human and corticosterone in rodents, are key hormones produced by the adrenal cortex that regulate innate immune responses. Pioneering work showed that a hormone from adrenal cortex was necessary to keep adrenolectomized animals alive after bacterial challenge (1), while a specific steroidal corticoid reversed the effects associated with adrenolectomy (2). These early studies suggest either these hormones (i.e., GCs) are necessary to mount an efficient self-defense response or counteract the aggressive side effects of this crucial reaction. While the first hypothesis will be discussed later, the second statement received attention when Phillip Hench assumed that arthritis remission could be related to high GCs blood levels. The later was verified to be true, as demonstrated by the reduction of rheumatoid arthritis symptoms upon treatment with cortisone [reviewed in Ref. (3, 4)]. An important step toward a molecular mechanism was the involvement of gene expression description in GCs anti-inflammatory effects, specifically the synthesis of an inhibitory protein or peptide (5–7). During the subsequent years, the main anti-inflammatory mechanism associated with GCs was the synthesis of Lipocortin 1 (Annexin A1; ANXA1), a phospholipase-A2 inhibitory protein that prevents the production of downstream inflammatory mediators prostaglandins and leukotrienes [reviewed in Ref. (3)]. The molecular cloning of steroid receptors increased the knowledge regarding GC receptor (GR) binding to the DNA and transcriptional control through GC response elements (GREs). These DNA sequences can mediate transactivation, as described above for ANXA1, or repression as well [reviewed in Ref. (8)]. Different modalities of GR interference in inflammatory signaling were reported, but one particular mechanism was considered more relevant to the understanding of GR functions during inflammation. This pathway drived the development of the concept of repression through tethering, which involves GR inhibitory physical interactions with nuclear activators of pro-inflammatory genes transcription (9–11). More importantly, this alternative paradigm opened the door to include other regulatory models and explore novel ligands with dissociated effects called selective GR agonists (SEGRAs) (also called dissociated GR ligands, and selective GR modulators; SEGRMs – specially in case of non-steroidal molecules) (12). GCs are known to interfere with innate immune signaling that promotes gene expression through engagement of Toll-like receptors (TLRs) and cytokine receptors, which leads to activation of transcription factors: nuclear factor (NF)-κB, activator protein (AP)-1, signal transducers and activators of transcription (STATs), interferon regulatory factors (IRFs), and others (13–16) (Figure 1). Here, we will discuss the perspectives of GR-mediated transcriptional activation or repression through varied mechanisms during the course of innate immune responses. We also aim to contextualize the different models of transcriptional control associated with GCs, which do not only suppresses inflammatory signaling, and point key discrepant observed outcomes and their interpretations.


Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses.

Xavier AM, Anunciato AK, Rosenstock TR, Glezer I - Front Endocrinol (Lausanne) (2016)

Global scheme of glucocorticoid signaling and transcriptional mechanism during inflammation. 1. Hypothalamus–pituitary–adrenal (HPA) signaling cascade upon stressors. CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotropic hormone; GCs, glucocorticoids. 2. The endogenous/synthetic GCs bind to glucocorticoid receptor (GR) and can act in two ways: non-genomic effects in cytoplasm or translocation into the nucleus, resulting in the modulation of the transcriptional responses (for example, the transactivation of anti-inflammatory genes). Alternatively, selective glucocorticoid receptor agonists (SEGRAs) can act majorly through tethering mechanism. 3. In the context of an inflammatory scenario, cytokines, DAMPS, and PAMPs bind to their respective receptors and activate pro-inflammatory transcription factors (TFs). These TFs translocate to the nucleus and increases the activity at pro-inflammatory genes promoters by GC–GR complex (composite sites, tethering, or compete for DNA-binding sites – not shown). 4. The four main transcriptional mechanisms involved in the inflammatory response: sGRE, nGRE, binding to composite sites and tethering. In the first two modes (sGRE and nGRE), the GC–GR complex modulates the transcription in a GRE-dependent manner activating or repressing genes, if accessible. In the last two modes (composite site and tethering), the GC–GR complex is recruited to GRE sites modulating gene expression in conjunction with TFs (composite site) or interacting directly with TFs (tethering) or coactivators (not shown). Please refer to main text for more details.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835445&req=5

Figure 1: Global scheme of glucocorticoid signaling and transcriptional mechanism during inflammation. 1. Hypothalamus–pituitary–adrenal (HPA) signaling cascade upon stressors. CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotropic hormone; GCs, glucocorticoids. 2. The endogenous/synthetic GCs bind to glucocorticoid receptor (GR) and can act in two ways: non-genomic effects in cytoplasm or translocation into the nucleus, resulting in the modulation of the transcriptional responses (for example, the transactivation of anti-inflammatory genes). Alternatively, selective glucocorticoid receptor agonists (SEGRAs) can act majorly through tethering mechanism. 3. In the context of an inflammatory scenario, cytokines, DAMPS, and PAMPs bind to their respective receptors and activate pro-inflammatory transcription factors (TFs). These TFs translocate to the nucleus and increases the activity at pro-inflammatory genes promoters by GC–GR complex (composite sites, tethering, or compete for DNA-binding sites – not shown). 4. The four main transcriptional mechanisms involved in the inflammatory response: sGRE, nGRE, binding to composite sites and tethering. In the first two modes (sGRE and nGRE), the GC–GR complex modulates the transcription in a GRE-dependent manner activating or repressing genes, if accessible. In the last two modes (composite site and tethering), the GC–GR complex is recruited to GRE sites modulating gene expression in conjunction with TFs (composite site) or interacting directly with TFs (tethering) or coactivators (not shown). Please refer to main text for more details.
Mentions: An inflammatory reaction relies on both fast triggering and tight control over intensity. Failure on fine-tuning immune cells activation and pro-inflammatory signaling can lead to unnecessary expended energy and tissue damage. Endogenous glucocorticoids (GCs), as cortisol in human and corticosterone in rodents, are key hormones produced by the adrenal cortex that regulate innate immune responses. Pioneering work showed that a hormone from adrenal cortex was necessary to keep adrenolectomized animals alive after bacterial challenge (1), while a specific steroidal corticoid reversed the effects associated with adrenolectomy (2). These early studies suggest either these hormones (i.e., GCs) are necessary to mount an efficient self-defense response or counteract the aggressive side effects of this crucial reaction. While the first hypothesis will be discussed later, the second statement received attention when Phillip Hench assumed that arthritis remission could be related to high GCs blood levels. The later was verified to be true, as demonstrated by the reduction of rheumatoid arthritis symptoms upon treatment with cortisone [reviewed in Ref. (3, 4)]. An important step toward a molecular mechanism was the involvement of gene expression description in GCs anti-inflammatory effects, specifically the synthesis of an inhibitory protein or peptide (5–7). During the subsequent years, the main anti-inflammatory mechanism associated with GCs was the synthesis of Lipocortin 1 (Annexin A1; ANXA1), a phospholipase-A2 inhibitory protein that prevents the production of downstream inflammatory mediators prostaglandins and leukotrienes [reviewed in Ref. (3)]. The molecular cloning of steroid receptors increased the knowledge regarding GC receptor (GR) binding to the DNA and transcriptional control through GC response elements (GREs). These DNA sequences can mediate transactivation, as described above for ANXA1, or repression as well [reviewed in Ref. (8)]. Different modalities of GR interference in inflammatory signaling were reported, but one particular mechanism was considered more relevant to the understanding of GR functions during inflammation. This pathway drived the development of the concept of repression through tethering, which involves GR inhibitory physical interactions with nuclear activators of pro-inflammatory genes transcription (9–11). More importantly, this alternative paradigm opened the door to include other regulatory models and explore novel ligands with dissociated effects called selective GR agonists (SEGRAs) (also called dissociated GR ligands, and selective GR modulators; SEGRMs – specially in case of non-steroidal molecules) (12). GCs are known to interfere with innate immune signaling that promotes gene expression through engagement of Toll-like receptors (TLRs) and cytokine receptors, which leads to activation of transcription factors: nuclear factor (NF)-κB, activator protein (AP)-1, signal transducers and activators of transcription (STATs), interferon regulatory factors (IRFs), and others (13–16) (Figure 1). Here, we will discuss the perspectives of GR-mediated transcriptional activation or repression through varied mechanisms during the course of innate immune responses. We also aim to contextualize the different models of transcriptional control associated with GCs, which do not only suppresses inflammatory signaling, and point key discrepant observed outcomes and their interpretations.

Bottom Line: GC's effects on inflammation are generally mediated through GC receptors (GRs).In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling.Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo , Brazil.

ABSTRACT
Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC's effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.

No MeSH data available.


Related in: MedlinePlus