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Tumor necrosis factor Inhibits glucocorticoid receptor function in mice a strong signal toward lethal shock

Tom Van Bogaert UGent, Sofie Vandevyver UGent, Lien Dejager UGent, Filip Van Hauwermeiren UGent, Iris Pinheiro UGent, Ioanna Petta UGent, David Engblom, Anna Kleyman, Guenther Schutz and Jan Tuckermann, et al. (2011) JOURNAL OF BIOLOGICAL CHEMISTRY. 286(30). p.26555-26567
abstract
As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNF alpha, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNF alpha-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNF alpha lethality was completely abolished when it was administered after TNF alpha stimulation, indicating compromised GR function upon TNF alpha challenge. TNF alpha-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNF alpha down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNF alpha also resulted in down-regulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNF alpha-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNF alpha inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNF alpha is intimately involved.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
INFLAMMATORY-BOWEL-DISEASE, STEROID-HORMONE RECEPTORS, NF-KAPPA-B, FACTOR-ALPHA, DOWN-REGULATION, C-JUN, MOLECULAR-MECHANISMS, ENDOTOXIC-SHOCK, TNF-ALPHA, TRANSCRIPTIONAL ACTIVATION
journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
J. Biol. Chem.
volume
286
issue
30
pages
26555 - 26567
Web of Science type
Article
Web of Science id
000293078200034
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
4.773 (2011)
JCR rank
66/286 (2011)
JCR quartile
1 (2011)
ISSN
0021-9258
DOI
10.1074/jbc.M110.212365
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1896374
handle
http://hdl.handle.net/1854/LU-1896374
date created
2011-09-01 12:49:55
date last changed
2012-06-26 14:32:24
@article{1896374,
  abstract     = {As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNF alpha, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNF alpha-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNF alpha lethality was completely abolished when it was administered after TNF alpha stimulation, indicating compromised GR function upon TNF alpha challenge. TNF alpha-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNF alpha down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNF alpha also resulted in down-regulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNF alpha-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNF alpha inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNF alpha is intimately involved.},
  author       = {Van Bogaert, Tom and Vandevyver, Sofie and Dejager, Lien and Van Hauwermeiren, Filip and Pinheiro, Iris and Petta, Ioanna and Engblom, David and Kleyman, Anna and Schutz, Guenther and Tuckermann, Jan and Libert, Claude},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keyword      = {INFLAMMATORY-BOWEL-DISEASE,STEROID-HORMONE RECEPTORS,NF-KAPPA-B,FACTOR-ALPHA,DOWN-REGULATION,C-JUN,MOLECULAR-MECHANISMS,ENDOTOXIC-SHOCK,TNF-ALPHA,TRANSCRIPTIONAL ACTIVATION},
  language     = {eng},
  number       = {30},
  pages        = {26555--26567},
  title        = {Tumor necrosis factor Inhibits glucocorticoid receptor function in mice a strong signal toward lethal shock},
  url          = {http://dx.doi.org/10.1074/jbc.M110.212365},
  volume       = {286},
  year         = {2011},
}

Chicago
Van Bogaert, Tom, Sofie Vandevyver, Lien Dejager, Filip Van Hauwermeiren, Iris Pinheiro, Ioanna Petta, David Engblom, et al. 2011. “Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice a Strong Signal Toward Lethal Shock.” Journal of Biological Chemistry 286 (30): 26555–26567.
APA
Van Bogaert, Tom, Vandevyver, S., Dejager, L., Van Hauwermeiren, F., Pinheiro, I., Petta, I., Engblom, D., et al. (2011). Tumor necrosis factor Inhibits glucocorticoid receptor function in mice a strong signal toward lethal shock. JOURNAL OF BIOLOGICAL CHEMISTRY, 286(30), 26555–26567.
Vancouver
1.
Van Bogaert T, Vandevyver S, Dejager L, Van Hauwermeiren F, Pinheiro I, Petta I, et al. Tumor necrosis factor Inhibits glucocorticoid receptor function in mice a strong signal toward lethal shock. JOURNAL OF BIOLOGICAL CHEMISTRY. 2011;286(30):26555–67.
MLA
Van Bogaert, Tom, Sofie Vandevyver, Lien Dejager, et al. “Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice a Strong Signal Toward Lethal Shock.” JOURNAL OF BIOLOGICAL CHEMISTRY 286.30 (2011): 26555–26567. Print.