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A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance

Valerie Gossye UGent, Dirk Elewaut UGent, Katrien Van Beneden UGent, Pieter Dewint UGent, Guy Haegeman UGent and Karolien De Bosscher UGent (2010) ANNALS OF THE RHEUMATIC DISEASES. 69(1). p.291-296
abstract
Background: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential. Methods: Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo). Results: Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects. Conclusion: Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
FACTOR-KAPPA-B, DEPENDENT DOWN-REGULATION, RHEUMATOID-ARTHRITIS, INTERLEUKIN-6 GENE, NUCLEAR RECEPTORS, CROSS-TALK, TRANSACTIVATION, TRANSCRIPTION, SYNOVIOCYTES, MECHANISMS
journal title
ANNALS OF THE RHEUMATIC DISEASES
Ann. Rheum. Dis.
volume
69
issue
1
pages
291 - 296
Web of Science type
Article
Web of Science id
000272594100052
JCR category
RHEUMATOLOGY
JCR impact factor
9.082 (2010)
JCR rank
1/29 (2010)
JCR quartile
1 (2010)
ISSN
0003-4967
DOI
10.1136/ard.2008.102871
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1095139
handle
http://hdl.handle.net/1854/LU-1095139
date created
2011-01-06 13:49:25
date last changed
2011-01-10 16:26:17
@article{1095139,
  abstract     = {Background: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential.
Methods: Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo).
Results: Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects.
Conclusion: Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids.},
  author       = {Gossye, Valerie and Elewaut, Dirk and Van Beneden, Katrien and Dewint, Pieter and Haegeman, Guy and De Bosscher, Karolien},
  issn         = {0003-4967},
  journal      = {ANNALS OF THE RHEUMATIC DISEASES},
  keyword      = {FACTOR-KAPPA-B,DEPENDENT DOWN-REGULATION,RHEUMATOID-ARTHRITIS,INTERLEUKIN-6 GENE,NUCLEAR RECEPTORS,CROSS-TALK,TRANSACTIVATION,TRANSCRIPTION,SYNOVIOCYTES,MECHANISMS},
  language     = {eng},
  number       = {1},
  pages        = {291--296},
  title        = {A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance},
  url          = {http://dx.doi.org/10.1136/ard.2008.102871},
  volume       = {69},
  year         = {2010},
}

Chicago
Gossye, Valerie, Dirk Elewaut, Katrien Van Beneden, Pieter Dewint, Guy Haegeman, and Karolien De Bosscher. 2010. “A Plant-derived Glucocorticoid Receptor Modulator Attenuates Inflammation Without Provoking Ligand-induced Resistance.” Annals of the Rheumatic Diseases 69 (1): 291–296.
APA
Gossye, V., Elewaut, D., Van Beneden, K., Dewint, P., Haegeman, G., & De Bosscher, K. (2010). A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance. ANNALS OF THE RHEUMATIC DISEASES, 69(1), 291–296.
Vancouver
1.
Gossye V, Elewaut D, Van Beneden K, Dewint P, Haegeman G, De Bosscher K. A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance. ANNALS OF THE RHEUMATIC DISEASES. 2010;69(1):291–6.
MLA
Gossye, Valerie, Dirk Elewaut, Katrien Van Beneden, et al. “A Plant-derived Glucocorticoid Receptor Modulator Attenuates Inflammation Without Provoking Ligand-induced Resistance.” ANNALS OF THE RHEUMATIC DISEASES 69.1 (2010): 291–296. Print.