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Differential mechanism of NF-κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts

Valerie Gossye UGent, Dirk Elewaut UGent, Nadia Bougarne UGent, Debby Bracke UGent, Serge Van Calenbergh UGent, Guy Haegeman UGent and Karolien De Bosscher UGent (2009) ARTHRITIS AND RHEUMATISM. 60(11). p.3241-3250
abstract
Objective. To investigate and compare the molecular mechanisms by which 2 glucocorticoid receptor (GR)-activating compounds, dexamethasone (DEX) and Compound A (CpdA), interfere with the NF-kappa B activation pathway in rheumatoid arthritis (RA) synovial cells. Methods. Quantitative polymerase chain reaction was performed to detect the tumor necrosis factor alpha (TNF alpha)-induced cytokine gene expression of interieukin-1 beta (IL-1 beta) and to investigate the effects of DEX and CpdA in RA fibroblast-like synoviocytes (FLS) transfected with small interfering RNA (siRNA) against GR (siGR) compared with nontransfected cells. Immunofluorescence analysis was used to detect the subcellular distribution of NF-kappa B (p65) under the various treatment conditions, and active DNA-bound p65 was measured using a TransAM assay and by chromatin immunoprecipitation analysis of IL-1 beta. Signaling pathways were studied via Western blotting of siGR-transfected cells, compared with nontransfected and nontargeting siRNA-transfected control cells, to detect the regulation of phospho-IKK, I kappa B alpha, phospho-p38, phospho-ERK, and phospho-JNK. Results. Both DEX and CpdA efficiently inhibited IL-1 beta gene expression in a GR-dependent manner. In addition, CpdA attenuated the TNF alpha-induced nuclear translocation and DNA binding of p65 in RA FLS, via the attenuation of IKK phosphorylation and subsequent I kappa B alpha degradation. CpdA also displayed profound effects on TNF alpha-induced MAPK activation. The effects of CpdA on TNF alpha-induced kinase activities occurred independently of the presence of GR. In sharp contrast, DEX did not affect TNF alpha-induced IKK phosphorylation, I kappa B alpha degradation, p65 nuclear translocation, or MAPK activation in RA FLS. Conclusion. DEX and CpdA display a dissimilar molecular mechanism of interaction with the NF-kappa B activation pathway ex vivo. A dual pathway, partially dependent and partially independent of GR (non-genomic), may explain the gene-inhibitory effects of CpdA in RA FLS.
Please use this url to cite or link to this publication:
author
organization
alternative title
Differential mechanism of NF-kappa B inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts
year
type
journalArticle (original)
publication status
published
subject
keyword
JOINT DESTRUCTION, INTERLEUKIN-6 GENE, MEDIATED REPRESSION, TRANSCRIPTIONAL ACTIVATION, COLLAGEN-INDUCED ARTHRITIS, TUMOR-NECROSIS-FACTOR, SYNOVIOCYTES, INFLAMMATORY CYTOKINE PRODUCTION, TRANSACTIVATION, PHOSPHORYLATION
journal title
ARTHRITIS AND RHEUMATISM
Arthritis Rheum.
volume
60
issue
11
pages
10 pages
Web of Science type
Article
Web of Science id
000271781400012
JCR category
RHEUMATOLOGY
JCR impact factor
7.332 (2009)
JCR rank
2/24 (2009)
JCR quartile
1 (2009)
ISSN
0004-3591
DOI
10.1002/art.24963
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
835808
handle
http://hdl.handle.net/1854/LU-835808
date created
2010-01-24 07:30:31
date last changed
2011-05-03 13:50:04
@article{835808,
  abstract     = {Objective. To investigate and compare the molecular mechanisms by which 2 glucocorticoid receptor (GR)-activating compounds, dexamethasone (DEX) and Compound A (CpdA), interfere with the NF-kappa B activation pathway in rheumatoid arthritis (RA) synovial cells.
Methods. Quantitative polymerase chain reaction was performed to detect the tumor necrosis factor alpha (TNF alpha)-induced cytokine gene expression of interieukin-1 beta (IL-1 beta) and to investigate the effects of DEX and CpdA in RA fibroblast-like synoviocytes (FLS) transfected with small interfering RNA (siRNA) against GR (siGR) compared with nontransfected cells. Immunofluorescence analysis was used to detect the subcellular distribution of NF-kappa B (p65) under the various treatment conditions, and active DNA-bound p65 was measured using a TransAM assay and by chromatin immunoprecipitation analysis of IL-1 beta. Signaling pathways were studied via Western blotting of siGR-transfected cells, compared with nontransfected and nontargeting siRNA-transfected control cells, to detect the regulation of phospho-IKK, I kappa B alpha, phospho-p38, phospho-ERK, and phospho-JNK.
Results. Both DEX and CpdA efficiently inhibited IL-1 beta gene expression in a GR-dependent manner. In addition, CpdA attenuated the TNF alpha-induced nuclear translocation and DNA binding of p65 in RA FLS, via the attenuation of IKK phosphorylation and subsequent I kappa B alpha degradation. CpdA also displayed profound effects on TNF alpha-induced MAPK activation. The effects of CpdA on TNF alpha-induced kinase activities occurred independently of the presence of GR. In sharp contrast, DEX did not affect TNF alpha-induced IKK phosphorylation, I kappa B alpha degradation, p65 nuclear translocation, or MAPK activation in RA FLS.
Conclusion. DEX and CpdA display a dissimilar molecular mechanism of interaction with the NF-kappa B activation pathway ex vivo. A dual pathway, partially dependent and partially independent of GR (non-genomic), may explain the gene-inhibitory effects of CpdA in RA FLS.},
  author       = {Gossye, Valerie and Elewaut, Dirk and Bougarne, Nadia and Bracke, Debby and Van Calenbergh, Serge and Haegeman, Guy and De Bosscher, Karolien},
  issn         = {0004-3591},
  journal      = {ARTHRITIS AND RHEUMATISM},
  keyword      = {JOINT DESTRUCTION,INTERLEUKIN-6 GENE,MEDIATED REPRESSION,TRANSCRIPTIONAL ACTIVATION,COLLAGEN-INDUCED ARTHRITIS,TUMOR-NECROSIS-FACTOR,SYNOVIOCYTES,INFLAMMATORY CYTOKINE PRODUCTION,TRANSACTIVATION,PHOSPHORYLATION},
  language     = {eng},
  number       = {11},
  pages        = {3241--3250},
  title        = {Differential mechanism of NF-\ensuremath{\kappa}B inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts},
  url          = {http://dx.doi.org/10.1002/art.24963},
  volume       = {60},
  year         = {2009},
}

Chicago
Gossye, Valerie, Dirk Elewaut, Nadia Bougarne, Debby Bracke, Serge Van Calenbergh, Guy Haegeman, and Karolien De Bosscher. 2009. “Differential Mechanism of NF-κB Inhibition by Two Glucocorticoid Receptor Modulators in Rheumatoid Arthritis Synovial Fibroblasts.” Arthritis and Rheumatism 60 (11): 3241–3250.
APA
Gossye, V., Elewaut, D., Bougarne, N., Bracke, D., Van Calenbergh, S., Haegeman, G., & De Bosscher, K. (2009). Differential mechanism of NF-κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts. ARTHRITIS AND RHEUMATISM, 60(11), 3241–3250.
Vancouver
1.
Gossye V, Elewaut D, Bougarne N, Bracke D, Van Calenbergh S, Haegeman G, et al. Differential mechanism of NF-κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts. ARTHRITIS AND RHEUMATISM. 2009;60(11):3241–50.
MLA
Gossye, Valerie, Dirk Elewaut, Nadia Bougarne, et al. “Differential Mechanism of NF-κB Inhibition by Two Glucocorticoid Receptor Modulators in Rheumatoid Arthritis Synovial Fibroblasts.” ARTHRITIS AND RHEUMATISM 60.11 (2009): 3241–3250. Print.