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

(2009) ARTHRITIS AND RHEUMATISM. 60(11). p.3241-3250
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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.
Keywords
JOINT DESTRUCTION, INTERLEUKIN-6 GENE, MEDIATED REPRESSION, TRANSCRIPTIONAL ACTIVATION, COLLAGEN-INDUCED ARTHRITIS, TUMOR-NECROSIS-FACTOR, SYNOVIOCYTES, INFLAMMATORY CYTOKINE PRODUCTION, TRANSACTIVATION, PHOSPHORYLATION

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MLA
Gossye, Valerie 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.
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.
Chicago author-date
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.
Chicago author-date (all authors)
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.
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.
IEEE
[1]
V. Gossye et al., “Differential mechanism of NF-κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts,” ARTHRITIS AND RHEUMATISM, vol. 60, no. 11, pp. 3241–3250, 2009.
@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}},
  keywords     = {{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-κB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts}},
  url          = {{http://dx.doi.org/10.1002/art.24963}},
  volume       = {{60}},
  year         = {{2009}},
}

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