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Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells

(2012) PLOS ONE. 7(4).
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Abstract
Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-gamma and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders.
Keywords
GENE-EXPRESSION, REGULATORY REGION, PLANT-ORIGIN, IL-5 PROMOTER, LINEAGE COMMITMENT, IN-VIVO, DNA-BINDING, TRANSCRIPTION FACTOR, ACTIVATED PROTEIN-KINASE, NF-KAPPA-B

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Chicago
Liberman, Ana C, Maria Antunica-Noguerol, Viviane Ferraz-de-Paula, Joao Palermo-Neto, Carla N Castro, Jimena Druker, Florian Holsboer, et al. 2012. “Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells.” Plos One 7 (4).
APA
Liberman, A. C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C. N., Druker, J., Holsboer, F., et al. (2012). Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells. PLOS ONE, 7(4).
Vancouver
1.
Liberman AC, Antunica-Noguerol M, Ferraz-de-Paula V, Palermo-Neto J, Castro CN, Druker J, et al. Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells. PLOS ONE. 2012;7(4).
MLA
Liberman, Ana C, Maria Antunica-Noguerol, Viviane Ferraz-de-Paula, et al. “Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells.” PLOS ONE 7.4 (2012): n. pag. Print.
@article{3060365,
  abstract     = {Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively.
Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-gamma and an increase in IL-5 production, respectively.
Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders.},
  articleno    = {e35155},
  author       = {Liberman, Ana C and Antunica-Noguerol, Maria and Ferraz-de-Paula, Viviane and Palermo-Neto, Joao and Castro, Carla N and Druker, Jimena and Holsboer, Florian and Perone, Marcelo J and Gerlo, Sarah and De Bosscher, Karolien and Haegeman, Guy and Arzt, Eduardo},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  language     = {eng},
  number       = {4},
  pages        = {11},
  title        = {Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells},
  url          = {http://dx.doi.org/10.1371/journal.pone.0035155},
  volume       = {7},
  year         = {2012},
}

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