title: Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock.
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.
authors.affiliation: Department for Molecular Biomedical Research, VIB, 9052 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van Bogaert
authors.forename: Sofie
authors.initials: S
authors.lastname: Vandevyver
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Iris
authors.initials: I
authors.lastname: Pinheiro
authors.forename: Ioanna
authors.initials: I
authors.lastname: Petta
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.forename: Anna
authors.initials: A
authors.lastname: Kleyman
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000235:genetics; D012769:Shock / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
chemical_list: D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha