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Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice A STRONG SIGNAL TOWARD LETHAL SHOCK
Ghent University, Belgium.
Ghent University, Belgium.
Ghent University, Belgium.
Ghent University, Belgium.
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2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 30, 26555-26567 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 286, no 30, 26555-26567 p.
National Category
Natural Sciences
URN: urn:nbn:se:liu:diva-74686DOI: 10.1074/jbc.M110.212365PubMedID: 21646349OAI: diva2:490247
Available from: 2012-02-04 Created: 2012-02-04 Last updated: 2012-03-19

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Engblom, David
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Cell BiologyFaculty of Health Sciences
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