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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 and Bart Lambrecht UGent, et al. (2012) JOURNAL OF IMMUNOLOGY. 188(7). p.3478-3487
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
TRANSACTIVATION, MICE, COMPOUND, TRANSCRIPTION, T-CELLS, MAP KINASE, PLANT-ORIGIN, GENE-EXPRESSION, MOLECULAR-MECHANISMS, NF-KAPPA-B
journal title
JOURNAL OF IMMUNOLOGY
J. Immunol.
volume
188
issue
7
pages
3478 - 3487
Web of Science type
Article
Web of Science id
000302150300061
JCR category
IMMUNOLOGY
JCR impact factor
5.52 (2012)
JCR rank
24/134 (2012)
JCR quartile
1 (2012)
ISSN
0022-1767
DOI
10.4049/jimmunol.1004227
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2095480
handle
http://hdl.handle.net/1854/LU-2095480
date created
2012-04-26 16:01:28
date last changed
2014-05-12 10:59:47
@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},
}

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.