Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock |
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Authors: | Van Bogaert Tom Vandevyver Sofie Dejager Lien Van Hauwermeiren Filip Pinheiro Iris Petta Ioanna Engblom David Kleyman Anna Schütz Günther Tuckermann Jan Libert Claude |
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Institution: | Department for Molecular Biomedical Research, VIB, 9052 Ghent, Belgium. |
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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 TNFα, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNFα-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNFα lethality was completely abolished when it was administered after TNFα stimulation, indicating compromised GR function upon TNFα challenge. TNFα-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNFα down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNFα 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 TNFα-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNFα 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 TNFα is intimately involved. |
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Keywords: | Cytokine Mouse Steroid Hormone Steroid Hormone Receptor Tumor Necrosis Factor (TNF) |
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