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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

Time-dependent evolution of inflammatory responses as orchestrated by multiple GR-dependent mechanism. At the first moment, after an inflammatory stimulus, acute-phase proteins (APP) and other genes are transcribed through transactivation, contributing to a pro-inflammatory response that correlates with a peak of endogenous GCs levels (red wave); examples of the transcriptional modalities are still poorly described. In a second moment, a subsequent endogenous GCs wave, or administration of synthetic GCs and SEGRAs (green dashed wave), correlates with the prevalence of anti-inflammatory response governed by transactivation (anti-inflammatory genes)/transrepression (pro-inflammatory genes) mechanisms. A decreased expression of pro-inflammatory genes, for instance, IL-1β (tethering) and possible C1q (nGRE), reinforce the anti-inflammatory modality ruled by sGRE mode (DUSP1, GILZ, etc.). No positive tethering mechanism was described for anti-inflammatory genes. In contrast, IRAK-M induction through composite site with NF-κB has been reported (see main text). The chromatin remodeling and different PTMs are present in both phase of inflammatory response, offering the relevant protein interactions and DNA-binding sites for GRs/TFs.
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Figure 2: Time-dependent evolution of inflammatory responses as orchestrated by multiple GR-dependent mechanism. At the first moment, after an inflammatory stimulus, acute-phase proteins (APP) and other genes are transcribed through transactivation, contributing to a pro-inflammatory response that correlates with a peak of endogenous GCs levels (red wave); examples of the transcriptional modalities are still poorly described. In a second moment, a subsequent endogenous GCs wave, or administration of synthetic GCs and SEGRAs (green dashed wave), correlates with the prevalence of anti-inflammatory response governed by transactivation (anti-inflammatory genes)/transrepression (pro-inflammatory genes) mechanisms. A decreased expression of pro-inflammatory genes, for instance, IL-1β (tethering) and possible C1q (nGRE), reinforce the anti-inflammatory modality ruled by sGRE mode (DUSP1, GILZ, etc.). No positive tethering mechanism was described for anti-inflammatory genes. In contrast, IRAK-M induction through composite site with NF-κB has been reported (see main text). The chromatin remodeling and different PTMs are present in both phase of inflammatory response, offering the relevant protein interactions and DNA-binding sites for GRs/TFs.

Mentions: Didactically, GR signaling may be divided into genomic (involving transcription regulation) and non-genomic. The later is faster and less characterized. Although probable, there are no strong evidences that GR engage relevant non-genomic signal transduction to repress pro-inflammatory signaling during innate immune responses (41, 42). GR genomic mechanisms that inhibit pro-inflammatory signaling include: (1) direct transcription of genes that will negatively interfere with pathways involved in the synthesis of inflammatory mediators; (2) direct repression of genes that contribute to immune cells activation; (3) negative interference in transcriptional events engaged by transcriptions factors that transduce pro-inflammatory signals; and (4) synergism between GR and other transcription factors activated during inflammation, ultimately promoting the induction of “anti-inflammatory” gene products. Examples of the first mechanism involves transcription of ANXA1, NFKBIA (IκBα), DUSP1 (MKP-1), GILZ, and ZFP36 (TPP). IκBα induction by GCs highjacks nuclear NF-κB, while MAP kinase phosphatase DUSP1 inactivates p38 kinase pro-inflammatory signaling, and tristetraproline (TPP) can destabilize many cytokine transcripts [reviewed in Ref. (43)]. A recent study showed that DUSP1 promotes activation of TPP destabilizing activity on Tnf, Il1b, and many other pro-inflammatory transcripts (44). For GILZ, we suggest a dedicated review (45). While direct repression (second mechanism) through nGREs during inflammation is not well characterized, some repressed genes associated with GCs anti-inflammatory effects through IR nGRE have been identified [C1qb, C3, Il6, etc., Ref. (31)]. However, an independent group was unable to recognize IR nGRE enrichment in their dataset (46). GR obstruction on the transactivation of pro-inflammatory genes activated by NF-κB/AP-1 (third mechanism) has been largely attributed to tethered transrepression, and to a lesser extent to composite sites or GR competition for DBS or limited coactivators (39, 43, 47). In the case of tethering, GR can associate with NF-κB and prevents the binding of IRF3 or positive transcription elongation factor b to the promoter. Conversely, GR recruits GRIP1 when tethered to AP-1, an event that may depend on nuclear thyroid hormone receptor interactor (48). We may expect that a “positive” GR tethering, recruiting coactivators, or activating the basal transcription machinery operates the expression of anti-inflammatory genes (fourth mechanism). It is not always clear if this is the case for some of the genes mentioned in the first mechanism. IRAK-M (IRAK3), which can block major TLRs pathways effectively, was recently described as a GR-induced gene through cooperation with NF-κB sites (49). Priming of chromatin state or presence and activity of coactivators/corepressor may impact greatly how GR modulates genes expression (50–53). We assume that all these transcriptional anti-inflammatory mechanisms prevail at late phases of an acute inflammatory reaction or when exogenous GR ligands are therapeutically delivered (Figure 2), which would be in agreement with time-dependent gene profiling assays (54).


Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses.

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

Time-dependent evolution of inflammatory responses as orchestrated by multiple GR-dependent mechanism. At the first moment, after an inflammatory stimulus, acute-phase proteins (APP) and other genes are transcribed through transactivation, contributing to a pro-inflammatory response that correlates with a peak of endogenous GCs levels (red wave); examples of the transcriptional modalities are still poorly described. In a second moment, a subsequent endogenous GCs wave, or administration of synthetic GCs and SEGRAs (green dashed wave), correlates with the prevalence of anti-inflammatory response governed by transactivation (anti-inflammatory genes)/transrepression (pro-inflammatory genes) mechanisms. A decreased expression of pro-inflammatory genes, for instance, IL-1β (tethering) and possible C1q (nGRE), reinforce the anti-inflammatory modality ruled by sGRE mode (DUSP1, GILZ, etc.). No positive tethering mechanism was described for anti-inflammatory genes. In contrast, IRAK-M induction through composite site with NF-κB has been reported (see main text). The chromatin remodeling and different PTMs are present in both phase of inflammatory response, offering the relevant protein interactions and DNA-binding sites for GRs/TFs.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Time-dependent evolution of inflammatory responses as orchestrated by multiple GR-dependent mechanism. At the first moment, after an inflammatory stimulus, acute-phase proteins (APP) and other genes are transcribed through transactivation, contributing to a pro-inflammatory response that correlates with a peak of endogenous GCs levels (red wave); examples of the transcriptional modalities are still poorly described. In a second moment, a subsequent endogenous GCs wave, or administration of synthetic GCs and SEGRAs (green dashed wave), correlates with the prevalence of anti-inflammatory response governed by transactivation (anti-inflammatory genes)/transrepression (pro-inflammatory genes) mechanisms. A decreased expression of pro-inflammatory genes, for instance, IL-1β (tethering) and possible C1q (nGRE), reinforce the anti-inflammatory modality ruled by sGRE mode (DUSP1, GILZ, etc.). No positive tethering mechanism was described for anti-inflammatory genes. In contrast, IRAK-M induction through composite site with NF-κB has been reported (see main text). The chromatin remodeling and different PTMs are present in both phase of inflammatory response, offering the relevant protein interactions and DNA-binding sites for GRs/TFs.
Mentions: Didactically, GR signaling may be divided into genomic (involving transcription regulation) and non-genomic. The later is faster and less characterized. Although probable, there are no strong evidences that GR engage relevant non-genomic signal transduction to repress pro-inflammatory signaling during innate immune responses (41, 42). GR genomic mechanisms that inhibit pro-inflammatory signaling include: (1) direct transcription of genes that will negatively interfere with pathways involved in the synthesis of inflammatory mediators; (2) direct repression of genes that contribute to immune cells activation; (3) negative interference in transcriptional events engaged by transcriptions factors that transduce pro-inflammatory signals; and (4) synergism between GR and other transcription factors activated during inflammation, ultimately promoting the induction of “anti-inflammatory” gene products. Examples of the first mechanism involves transcription of ANXA1, NFKBIA (IκBα), DUSP1 (MKP-1), GILZ, and ZFP36 (TPP). IκBα induction by GCs highjacks nuclear NF-κB, while MAP kinase phosphatase DUSP1 inactivates p38 kinase pro-inflammatory signaling, and tristetraproline (TPP) can destabilize many cytokine transcripts [reviewed in Ref. (43)]. A recent study showed that DUSP1 promotes activation of TPP destabilizing activity on Tnf, Il1b, and many other pro-inflammatory transcripts (44). For GILZ, we suggest a dedicated review (45). While direct repression (second mechanism) through nGREs during inflammation is not well characterized, some repressed genes associated with GCs anti-inflammatory effects through IR nGRE have been identified [C1qb, C3, Il6, etc., Ref. (31)]. However, an independent group was unable to recognize IR nGRE enrichment in their dataset (46). GR obstruction on the transactivation of pro-inflammatory genes activated by NF-κB/AP-1 (third mechanism) has been largely attributed to tethered transrepression, and to a lesser extent to composite sites or GR competition for DBS or limited coactivators (39, 43, 47). In the case of tethering, GR can associate with NF-κB and prevents the binding of IRF3 or positive transcription elongation factor b to the promoter. Conversely, GR recruits GRIP1 when tethered to AP-1, an event that may depend on nuclear thyroid hormone receptor interactor (48). We may expect that a “positive” GR tethering, recruiting coactivators, or activating the basal transcription machinery operates the expression of anti-inflammatory genes (fourth mechanism). It is not always clear if this is the case for some of the genes mentioned in the first mechanism. IRAK-M (IRAK3), which can block major TLRs pathways effectively, was recently described as a GR-induced gene through cooperation with NF-κB sites (49). Priming of chromatin state or presence and activity of coactivators/corepressor may impact greatly how GR modulates genes expression (50–53). We assume that all these transcriptional anti-inflammatory mechanisms prevail at late phases of an acute inflammatory reaction or when exogenous GR ligands are therapeutically delivered (Figure 2), which would be in agreement with time-dependent gene profiling assays (54).

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