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  • DKFZ Publication Database  (2)
  • GENE-EXPRESSION  (2)
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  • DKFZ Publication Database  (2)
  • 1
    Keywords: EXPRESSION ; DISEASE ; liver ; GENE-EXPRESSION ; NF-KAPPA-B ; mechanisms ; C-JUN ; DOWN-REGULATION ; TNF-ALPHA ; inflammation ; INFLAMMATORY-BOWEL-DISEASE ; FACTOR-ALPHA ; MOLECULAR-MECHANISMS ; TRANSCRIPTIONAL ACTIVATION ; STEROID-HORMONE RECEPTORS ; ENDOTOXIC-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 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
    Type of Publication: Journal article published
    PubMed ID: 21646349
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  • 2
    Keywords: EXPRESSION ; IN-VITRO ; SURVIVAL ; MODEL ; GENE-EXPRESSION ; MICE ; ACTIVATION ; MAP KINASE ; DNA-BINDING ; KAPPA-B ; REPRESSION ; INFLAMMATORY RESPONSES ; dexamethasone ; CLP ; GR ; IL-1 beta ; PHOSPHATASE-1
    Abstract: Sepsis is controlled by endogenous glucocorticoids (GCs). Previous studies provided evidence that crosstalk of the monomeric GC receptor (GR) with proinflammatory transcription factors is the crucial mechanism underlying the suppressive GC effect. Here we demonstrate that mice with a dimerization-deficient GR (GR(dim)) are highly susceptible to sepsis in 2 different models, namely cecal ligation and puncture and lipopolysaccharide (LPS)-induced septic shock. TNF-alpha is normally regulated in these mice, but down-regulation of IL-6 and IL-1 beta is diminished. LPS-treated macrophages derived from GR(dim) mice are largely resistant to GC actions in vitro in terms of morphology, surface marker expression, and gene expression. Treatment with recombinant IL-1 receptor antagonist improved survival of GR(dim) mice and mice lacking the GR in macrophages (GR(LysMCre)) mice. This suggests that regulation of IL-1 beta in macrophages by GCs is pivotal to control sepsis.-Kleiman, A., Hubner, S., Rodriguez Parkitna, J. M., Neumann, A., Hofer, S., Weigand, M. A., Bauer, M., Schmid, W., Schutz, G., Libert, C., Reichardt, H. M., Tuckermann, J. P. Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages.
    Type of Publication: Journal article published
    PubMed ID: 22042221
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