Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

Liberman, Ana C.; Antunica-Noguerol, María; Ferraz-de-Paula, V.; Palermo-Neto, João; Castro, Carla; Druker, Jimena; Holsboer, Florian; Perone, Marcelo J.; Gerlo, Sarah; Bosscher, Karolien De; Haegeman, Guy; Arzt, Eduardo

doi:10.1371/journal.pone.0035155

Cited by 34 publications

(44 citation statements)

References 51 publications

(105 reference statements)

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“…The observation that CpdA inhibits the expression of steroid-resistant chemokines at the mRNA level (Figure 2) strongly suggests that CpdA acted at the transcriptional level. Previous reports showed that CpdA repressed the function of different transcription factors, including NF-kB or AP-1 (defined as transrepression) (19,34,40,41), STAT6 (22), and T-bet (39). We now provide the first evidence that CpdA inhibits the activation of IRF-1 by affecting its nuclear accumulation ( Figure 6).…”

Section: Discussionsupporting

confidence: 59%

“…Increasing the incubation time with CpdA for up to 6 hours did not induce GRa nuclear translocation in ASM cells (Figure 4). Because the implication of GRa in CpdA antiinflammatory actions was also demonstrated using receptor antagonists RU38486 (39) or RU486 (28), we used the same approach but failed to see any preventive effect of RU486 on CpdA responses (Figure 4), providing strong evidence against a role of GRa in CpdA action. Our conclusion is in agreement with one previous study showing that CpdA action was still preserved in cells lacking functional GRa (GRa-deficient mouse embryonic fibroblasts or WEHI-7.1 cells transfected with siRNA GRa) (20).…”

Section: Discussionmentioning

confidence: 99%

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Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Gavrila

Chachi

Tliba

et al. 2015

Am J Respir Cell Mol Biol

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Preclinical models of human conditions including asthma showed the therapeutic potential of Compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRa) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokineinduced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNF-a/IFN-g for 24 hours in the presence or absence of CpdA. ELISA and quantitative PCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRa by CpdA was assessed by quantitative PCR, immunostaining, and receptor antagonism using RU486. An effect of CpdA on the transcription factor interferon regulatory factor 1 (IRF-1) was investigated using immunoblot, immunostaining, and small interfering RNA (siRNA) knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of GC-induced Leucine Zipper while transiently inducing mitogen-activated protein kinase phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRa nuclear translocation, nor was it prevented by RU486 antagonism. Activation of IRF-1 by TNF-a/IFN-g was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time, we show that CpdA inhibits the production of GC-resistant chemokines via GRa-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA-sensitive pathways in ASM cells represents an alternative therapeutic approach to treat GC resistance in asthma.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Gavrila

Chachi

Tliba

et al. 2015

Am J Respir Cell Mol Biol

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“…S11). Intriguingly, the Ser425Gly mutation has been widely studied in the context of hGR and shown to have deleterious effects on the repression of T-bet, AP-1, and NF-κB by hGR (29)(30)(31)(32), suggesting DNA binding-mediated effects play a larger role in proinflammatory transcriptional repression by the GR than has been previously assumed.…”

Section: Dbd-ngre Binding and Subsequent Repression Is A Feature Of Thementioning

confidence: 99%

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hudson

Kossmann

Vera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Many genomes contain families of paralogs-proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response elementbinding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.evolution | glucocorticoid | epistasis | steroid receptors

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“…EL4 T cells (murine T cell lymphoma) were transfected by electroporation [23,24]. Luciferase activity was measured using the luciferase measure kit (Promega).…”

Section: Transient Transfections and Luciferase Activitymentioning

confidence: 99%

Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes

Castro

Tabarrozzi

Winnewisser

et al. 2014

Clinical and Experimental Immunology

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SummaryType 1 diabetes (T1DM) is a T cell-mediated autoimmune disease that selectively destroys pancreatic β cells. The only possible cure for T1DM is to control autoimmunity against β cell-specific antigens. We explored whether the natural compound curcumin, with anti-oxidant and anti-inflammatory activities, might down-regulate the T cell response that destroys pancreatic β cells to improve disease outcome in autoimmune diabetes. We employed two accelerated autoimmune diabetes models: (i) cyclophosphamide (CYP) administration to non-obese diabetic (NOD) mice and (ii) adoptive transfer of diabetogenic splenocytes into NODscid mice. Curcumin treatment led to significant delay of disease onset, and in some instances prevented autoimmune diabetes by inhibiting pancreatic leucocyte infiltration and preserving insulin-expressing cells. To investigate the mechanisms of protection we studied the effect of curcumin on key immune cell populations involved in the pathogenesis of the disease. Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-γ production through modulation of T-box expressed in T cells (T-bet), a key transcription factorfor proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Also, curcumin reduces nuclear factor (NF)-κB activation in T cell receptor (TCR)-stimulated NOD lymphocytes. In addition, curcumin impairs the T cell stimulatory function of dendritic cells with reduced secretion of proinflammatory cytokines and nitric oxide (NO) and low surface expression of co-stimulatory molecules, leading to an overall diminished antigen-presenting cell activity. These in-vitro effects correlated with ex-vivo analysis of cells obtained from curcumin-treated mice during the course of autoimmune diabetes. These findings reveal an effective therapeutic effect of curcumin in autoimmune diabetes by its actions on key immune cells responsible for β cell death.

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Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

Cited by 34 publications

References 51 publications

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes

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