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  • GENE  (2)
  • mechanisms  (2)
  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; CELL ; MODEL ; MODELS ; GENE ; transcription ; METABOLISM ; DIFFERENTIATION ; MICE ; ACTIVATION ; DNA ; MECHANISM ; MARKER ; primary ; INDUCTION ; KERATINOCYTES ; mechanisms ; SKIN ; MATURATION ; MOUSE ; NUMBER ; DNA-BINDING ; SIGNALING PATHWAY ; epidermis ; ARCHITECTURE ; desmosomes ; USA ; LOSSES ; HOMEOSTASIS ; BARRIER ; CASPASE-14 ; EPIDERMAL-KERATINOCYTES ; FETAL MOUSE
    Abstract: To investigate the contribution of the glucocorticoid receptor (GR) in skin development and the mechanisms underlying this function, we have analyzed two mouse models in which GR has been functionally inactivated: the knockout GR(-/-) mice and the dimerization mutant GR(dim/dim) that mediates defective DNA binding-dependent transcription. Because GR null mice die perinatally, we evaluated skin architecture of late embryos by histological, immunohistochemical, and electron microscopy studies. Loss of function of GR resulted in incomplete epidermal stratification with dramatically abnormal differentiation of GR(-/-), but not GR(+/-) embryos, as demonstrated by the lack of loricrin, filaggrin, and involucrin markers. Skin sections of GR(-/-) embryos revealed edematous basal and lower spinous cells, and electron micrographs showed increased intercellular spaces between keratinocytes and reduced number of desmosomes. The absent terminal differentiation in GR(-/-) embryos correlated with an impaired activation of caspase-14, which is required for the processing of profilaggrin into filaggrin at late embryo stages. Accordingly, the skin barrier competence was severely compromised in GR(-/-) embryos. Cultured mouse primary keratinocytes from GR(-/-) mice formed colonies with cells of heterogeneous size and morphology that showed increased growth and apoptosis, indicating that GR regulates these processes in a cell-autonomous manner. The activity of ERK1/2 was constitutively augmented in GR(-/-) skin and mouse primary keratinocytes relative to wild type, which suggests that GR modulates skin homeostasis, at least partially, by antagonizing ERK function. Moreover, the epidermis of GR(+/dim) and GR(dim/dim) embryos appeared normal, thus suggesting that DNA-binding-independent actions of GR are sufficient to mediate epidermal and hair follicle development during embryogenesis
    Type of Publication: Journal article published
    PubMed ID: 18039792
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  • 2
    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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  • 3
    Keywords: CELLS ; IN-VIVO ; GENE ; GENE-EXPRESSION ; MICE ; IFN-GAMMA ; MOUSE ; CD4(+) T-CELLS ; CYTOKINE ; DEFICIENCY ; IL-7 ; HOMEOSTATIC PROLIFERATION ; GUT ; INTESTINAL EPITHELIAL-CELLS ; Commensal microflora ; Intestinal epithelial cells
    Abstract: IL-7 is a major regulator of lymphocyte homeostasis; however, little is known about the mechanisms that regulate IL-7 production. To study Il7 gene regulation in vivo, we generated a novel IL-7-reporter mouse, which allows the non-invasive quantification of Il7 gene activity in live mice and, additionally, the simultaneous activation/inactivation of target genes in IL-7-producing cells. With these IL-7-reporter mice, we identify thymus, skin and intestine as major sources of IL-7 in vivo. Importantly, we show that IFN-gamma and the commensal microflora promote steady-state IL-7 production in the intestine. Furthermore, we demonstrate that the blockade of IFN-gamma signaling in intestinal epithelial cells strongly reduces their IFN-gamma-driven IL-7 production. In summary, our data suggest a feedback loop in which commensal bacteria drive IFN-gamma production by lymphocytes, which in turn promotes epithelial cell IL-7 production and the survival of IL-7-dependent lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 20690180
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