Mechanisms of glucocorticoid signalling
ABSTRACT It has become increasingly clear that glucocorticoid signalling not only comprises the binding of the glucocorticoid receptor (GR) to its response element (GRE), but also involves indirect regulation glucocorticoid-responsive genes by regulating or interacting with other transcription factors. In addition, they can directly regulate gene expression by binding to negative glucocorticoid response elements (nGREs), to simple GREs, to GREs, or to GREs and GRE half sites (GRE1/2s) that are part of a regulatory unit. A response unit allows a higher level of glucocorticoid induction than simple GREs and, in addition, allows the integration of tissue-specific information with the glucocorticoid response. Presumably, the complexity of such a glucocorticoid response unit (GRU) depends on the number of pathways that integrate at this unit. Because GRUs are often located at distant sites relative to the transcription-start site, the GRU has to find a way to communicate with the basal-transcription machinery. We propose that the activating signal of a distal enhancer can be relayed onto the transcription-initiation complex by coupling elements located proximal to the promoter.
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- "in regions that promote stress recovery (Bale et al., 2000; Coste et al., 2000), including the LS (Victoria et al. 2013, unpublished data). Given that corticosterone-GR complexes transcriptionally regulate the central expression of CRFRs (Schoneveld et al., 2004), such changes are expected. "
ABSTRACT: Less than 60% of infants undergoing invasive procedures in the NICU receive analgesic therapy. These infants show long-term decreases in pain sensitivity and cortisol reactivity. In rats we have previously shown that inflammatory pain experienced on the day of birth significantly decreases adult somatosensory thresholds and responses to anxiety- and stress-provoking stimuli. These long-term changes in pain and stress responsiveness are accompanied by 2-fold increases in central met-enkephalin and ß-endorphin expression. However, the time course over which these changes in central opioid peptide expression occur, relative to the time of injury, are not known. The present studies were conducted to determine if the observed changes in adult opioid peptide expression were present within the first postnatal week following injury. The impact of neonatal inflammation on plasma corticosterone, a marker for stress reactivity, was also determined. Brain, spinal cord and trunk blood were harvested at 24 hrs, 48 hrs and 7 days following intraplantar administration of the inflammatory agent carrageenan on the day of birth. Radioimmunoassay was used to determine plasma corticosterone and met-enkephalin and ß-endorphin levels within the forebrain, cortex, midbrain, and spinal cord. Within 24 hrs of injury met-enkephalin levels were significantly increased in the midbrain, but decreased in the spinal cord and cortex; forebrain ß-endorphin levels were significantly increased as a result of early life pain. Corticosterone levels were also significantly increased. At 7 days post-injury, opioid peptides remained elevated relative to controls, suggesting a time point by which injury induced changes become programmed and permanent. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.Developmental Neurobiology 01/2014; 74(1). DOI:10.1002/dneu.22129 · 4.19 Impact Factor
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- "These receptors, like other nuclear receptors, are transcription factors. One of the main mechanisms includes direct effects on gene expression by the binding to glucocorticoid responsive elements (GRE) in the promoter region of target genes to constitute a glucocorticoid response unit to activate the transcription (Scheidereit et al. 1983; Karin 1998; Schoneveld et al. 2004). In addition, it has been reported that glucocorticoid receptors also participate in chromatin remodeling and interact with coregulators, resulting in changes in the expression of genes that do not have GREs in the promoter (McEwan et al. 1997; Deroo and Archer 2001; Lonard and O'Malley 2007). "
ABSTRACT: Chronic stress and dysfunction of the serotonergic system in the brain have been considered as two of the major risks for development of depression. In the present study, adult Fischer 344 rats were subjected to a regimen of chronic social defeat (CSD). To mimic stressful conditions some rats were not exposed to CSD but instead treated with corticosterone (CORT) in oral solution while maintained in their home cage. Protein levels of the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN), hippocampus, frontal cortex and amygdala were examined by western blotting or immunofluorescence staining. The results showed that CSD up-regulated SERT protein levels in the DRN, hippocampus, frontal cortex and amygdala regions. This upregulation was abolished or prevented by adrenalectomy, or treatment with antagonists of corticosteroid receptors mifepristone and spironolactone, alone or in combination. Similarly, up-regulated SERT protein levels in these brain regions were also observed in rats treated with oral CORT ingestion, which was analogously prevented by treatment with mifepristone and spironolactone. Furthermore, both CSD- and CORT-induced upregulation of SERT protein levels in the DRN and three brain regions were attenuated by simultaneous treatment with fluoxetine, an antidepressant that specifically inhibits serotonin reuptake. The results indicate that upregulation in SERT protein levels in the DRN and forebrain limbic structures caused by CSD regimen was mainly motivated by CORT through corticosteroid receptors. The present findings demonstrate that chronic stress is closely correlated with the serotonergic system by acting on the regulation of the SERT expression in the DRN and its projection regions, which may contribute to the development of depression. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12055.Journal of Neurochemistry 10/2012; 123(6). DOI:10.1111/jnc.12055 · 4.24 Impact Factor
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- "The molecular mechanism underlying this distinction is not clear. Effects of 5aTHB to induce IL-10 as well as suppress TNF-a and IL-6 suggest signalling mediated by 'GR-protein' interaction of GR with STAT3 (Unterberger et al., 2008) and also NFkB and AP-1 (Schoneveld et al., 2004). The lack of effect of 5aTHB on genes encoding proteins such as TAT, PEPCK and AGT suggests that 5aTHB does not induce GR effects mediated through homodimerization and 'positive' GRE binding (Grange et al., 1991; Sugiyama et al., 1998). "
ABSTRACT: Dissociating anti-inflammatory efficacy from the metabolic side effects of glucocorticoids is an attractive therapeutic goal. 5α-Tetrahydro-corticosterone (5αTHB), produced from corticosterone by 5α-reductases, activates glucocorticoid receptors. This study compares the effects of 5αTHB on inflammation and metabolism in vitro and in vivo. Suppression of cytokine release by 5αTHB and corticosterone were studied following LPS activation of mouse bone marrow derived macrophages. In vivo the efficacy of these steroids to dysregulate metabolic homeostasis and modulate immune suppression and the responses to thioglycollate-induced peritonitis in C57BL/6 mice were studied following acute injection (1.5-15 mg) and chronic infusion (50 µg·day(-1) , 14 days). In macrophages, 5αTHB increased secretion of IL-10 similarly to corticosterone (180%, 340%; data are % vehicle, treated with 5αTHB and corticosterone, respectively) and suppressed LPS-induced secretion of TNF-α (21.9%, 74.2%) and IL-6 (16.4%, 69.4%). In mice with thioglycollate-induced peritonitis, both 5αTHB and corticosterone reduced the numbers of neutrophils (58.6%, 49.9%) and inflammatory monocytes (69.5%, 96.4%), and also suppressed MCP-1 (48.7%, 80.9%) and IL-6 (53.5%, 86.7%) in peritoneal exudate. In mice chronically infused with 5αTHB and corticosterone LPS-induced production of TNF-α from whole blood was suppressed to the same degree (63.2%, 37.2%). However, in contrast to corticosterone, 5αTHB did not induce body weight loss, increase blood pressure or induce hyperinsulinaemia. 5αTHB has anti-inflammatory effects in vitro and in vivo. At doses with equivalent anti-inflammatory efficacy to corticosterone, 5αTHB did not induce metabolic toxicity and thus may be a prototype for a safer anti-inflammatory drug.British Journal of Pharmacology 05/2011; 164(6):1661-71. DOI:10.1111/j.1476-5381.2011.01465.x · 4.99 Impact Factor