Advanced search
1 file | 2.26 MB

A dissociated glucocorticoid receptor modulator reduces airway hyperresponsiveness and inflammation in a mouse model of asthma

Laurent L Reber, François Daubeuf, Maud Plantinga (UGent) , Lode De Cauwer (UGent) , Sarah Gerlo (UGent) , Wim Waelput (UGent) , Serge Van Calenbergh (UGent) , Jan Tavernier (UGent) , Guy Haegeman (UGent) , Bart Lambrecht (UGent) , et al.
(2012) JOURNAL OF IMMUNOLOGY. 188(7). p.3478-3487
Author
Organization
Project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-kappa B and its subsequent recruitment onto the I kappa B alpha promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.
Keywords
TRANSACTIVATION, MICE, COMPOUND, TRANSCRIPTION, T-CELLS, MAP KINASE, PLANT-ORIGIN, GENE-EXPRESSION, MOLECULAR-MECHANISMS, NF-KAPPA-B

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 2.26 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Reber, Laurent L, François Daubeuf, Maud Plantinga, Lode De Cauwer, Sarah Gerlo, Wim Waelput, Serge Van Calenbergh, et al. 2012. “A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma.” Journal of Immunology 188 (7): 3478–3487.
APA
Reber, L. L., Daubeuf, F., Plantinga, M., De Cauwer, L., Gerlo, S., Waelput, W., Van Calenbergh, S., et al. (2012). A dissociated glucocorticoid receptor modulator reduces airway hyperresponsiveness and inflammation in a mouse model of asthma. JOURNAL OF IMMUNOLOGY, 188(7), 3478–3487.
Vancouver
1.
Reber LL, Daubeuf F, Plantinga M, De Cauwer L, Gerlo S, Waelput W, et al. A dissociated glucocorticoid receptor modulator reduces airway hyperresponsiveness and inflammation in a mouse model of asthma. JOURNAL OF IMMUNOLOGY. 2012;188(7):3478–87.
MLA
Reber, Laurent L, François Daubeuf, Maud Plantinga, et al. “A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma.” JOURNAL OF IMMUNOLOGY 188.7 (2012): 3478–3487. Print.
@article{2095480,
  abstract     = {The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-kappa B and its subsequent recruitment onto the I kappa B alpha promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.},
  author       = {Reber, Laurent L and Daubeuf, Fran\c{c}ois and Plantinga, Maud and De Cauwer, Lode and Gerlo, Sarah and Waelput, Wim and Van Calenbergh, Serge and Tavernier, Jan and Haegeman, Guy and Lambrecht, Bart and Frossard, Nelly and De Bosscher, Karolien},
  issn         = {0022-1767},
  journal      = {JOURNAL OF IMMUNOLOGY},
  keyword      = {TRANSACTIVATION,MICE,COMPOUND,TRANSCRIPTION,T-CELLS,MAP KINASE,PLANT-ORIGIN,GENE-EXPRESSION,MOLECULAR-MECHANISMS,NF-KAPPA-B},
  language     = {eng},
  number       = {7},
  pages        = {3478--3487},
  title        = {A dissociated glucocorticoid receptor modulator reduces airway hyperresponsiveness and inflammation in a mouse model of asthma},
  url          = {http://dx.doi.org/10.4049/jimmunol.1004227},
  volume       = {188},
  year         = {2012},
}

Altmetric
View in Altmetric
Web of Science
Times cited: