Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells
- Author
- Ana C Liberman, Maria Antunica-Noguerol, Viviane Ferraz-de-Paula, Joao Palermo-Neto, Carla N Castro, Jimena Druker, Florian Holsboer, Marcelo J Perone, Sarah Gerlo (UGent) , Karolien De Bosscher (UGent) , Guy Haegeman (UGent) and Eduardo Arzt
- Organization
- 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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Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-3060365
- MLA
- Liberman, Ana C., et al. “Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-Bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells.” PLOS ONE, vol. 7, no. 4, 2012, doi:10.1371/journal.pone.0035155.
- APA
- Liberman, A. C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C. N., Druker, J., … Arzt, E. (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). https://doi.org/10.1371/journal.pone.0035155
- Chicago author-date
- 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). https://doi.org/10.1371/journal.pone.0035155.
- Chicago author-date (all authors)
- Liberman, Ana C, Maria Antunica-Noguerol, Viviane Ferraz-de-Paula, Joao Palermo-Neto, Carla N Castro, Jimena Druker, Florian Holsboer, Marcelo J Perone, Sarah Gerlo, Karolien De Bosscher, Guy Haegeman, and Eduardo Arzt. 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). doi:10.1371/journal.pone.0035155.
- 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).
- IEEE
- [1]A. C. Liberman et al., “Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells,” PLOS ONE, vol. 7, no. 4, 2012.
@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}}, keywords = {{GENE-EXPRESSION,REGULATORY REGION,PLANT-ORIGIN,IL-5 PROMOTER,LINEAGE COMMITMENT,IN-VIVO,DNA-BINDING,TRANSCRIPTION FACTOR,ACTIVATED PROTEIN-KINASE,NF-KAPPA-B}}, 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://doi.org/10.1371/journal.pone.0035155}}, volume = {{7}}, year = {{2012}}, }
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