Mechanisms of glucocorticoid receptor signaling during inflammation

Smoak, Kathleen; Cidlowski, John A.

doi:10.1016/j.mad.2004.06.010

Cited by 358 publications

(330 citation statements)

References 73 publications

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“…Once activated by GCs, GRs forms homodimers and translocate into the nucleus, where they ultimately bind to specific GRE on gene promoters to regulate transcription (Hayashi et al 2004, Smoak & Cidlowski 2004. However, this mechanism dose not explains all the actions of GCs.…”

Section: Discussionmentioning

confidence: 99%

Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

Yang¹,

Guo²,

Zhu³

et al. 2007

Journal of Endocrinology

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The amount of cortisol available to its receptors is increased by the pre-receptor enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) which converts cortisone to cortisol. We examined the molecular mechanisms of the feedback effect of cortisol on 11b-HSD1 mRNA expression in human amnion fibroblasts. Our data showed that cortisol-induced 11b-HSD1 mRNA expression dose dependently in amnion fibroblasts, which could be completely blocked both by the mRNA transcription inhibitor 5,6-dichlorobenzimidazole riboside and by the glucocorticoid receptor (GR) antagonist RU486, and partially blocked by global inhibition of CCAAT/enhancerbinding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression CMV500 plasmid (AC/EBP) into the cells. Likewise, the induction of the promoter activity by cortisol could also be completely blocked by RU486 and partially by AC/EBP transfection. Progressive 5 0 deletion of the 11b-HSD1 promoter located the region responsible for cortisol's induction within K204 bp upstream to the transcription start site. Specific nucleotide mutations of the putative glucocorticoid responsive element or CCAAT in this promoter region attenuated the induction by cortisol. Moreover, chromatin immunoprecipitation assay and electrophoretic mobility shift assay showed that GR and C/EBPa but not C/EBPb could bind this promoter region upon cortisol stimulation of amnion fibroblasts. In conclusion, we demonstrated that GR and C/EBPa were involved in cortisol-induced 11b-HSD1 mRNA expression via binding to 11b-HSD1 promoter in amnion fibroblasts, which may cast a feed-forward production of cortisol in the fetal membranes at the end of gestation.

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Section: Discussionmentioning

confidence: 99%

Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

Yang¹,

Guo²,

Zhu³

et al. 2007

Journal of Endocrinology

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“…Moreover, JU may act on more than 10 pathways, which may contribute to the pure synergistic mechanism (Supplement Table 2). Some of these new pathways were involved in inflammatory immunity (IL-18 Signaling, Actin Cytoskeleton Signaling, Glucocorticoid Receptor Signaling, Lymphotoxin B Receptor Signaling, and IL-15 Signaling [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] [69][70][71][72][73][74][75][76][77] . Therefore, we propose that the pure synergistic mechanism is focused on inflammation, immune responses, apoptosis, and nervous system development ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

Wang

et al. 2015

Acta Pharmacol Sin

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Aim: Our previous studies have showed that ursodeoxycholic acid (UA) and jasminoidin (JA) effectively reduce cerebral infarct volume in mice. In this study we explored the pure synergistic mechanism of these compounds in treatment of mouse cerebral ischemia, which was defined as synergistic actions specific for phenotype variations after excluding interference from ineffective compounds. Methods: Mice with focal cerebral ischemia were treated with UA, JA or a combination JA and UA (JU). Concha margaritifera (CM) was taken as ineffective compound. Cerebral infarct volume of the mice was determined, and the hippocampi were taken for microarray analysis. Particular signaling pathways and biological functions were enriched based on differentially expressed genes, and corresponding networks were constructed through Ingenuity Pathway Analysis. Results: In phenotype analysis, UA, JA, and JU significantly reduced the ischemic infarct volume with JU being superior to UA or JA alone, while CM was ineffective. As a result, 4 pathways enriched in CM were excluded. Core pathways in the phenotype-positive groups (UA or JA) were involved in neuronal homeostasis and neuropathology. JU-contributing pathways included all UA-contributing and the majority (71.7%) of JA-contributing pathways, and 10 new core pathways whose effects included inflammatory immunity, apoptosis and nervous system development. The functions of JU group included all functions of JA group, the majority (93.1%) of UA-contributing functions, and 3 new core functions, which focused on physiological system development and function. Conclusion: The pure synergism between UA and JA underlies 10 new core pathways and 3 new core functions, which are involved in inflammation, immune responses, apoptosis and nervous system development.

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“…This screen was initially designed to discover GR modulators based on changes in activity of 3 promoters that are activated by GR but it left uncertain whether leads would alter GR physiology. GR is a well-known suppressor of TNF-␣ activity, an important aspect of the antiinflammatory effects of glucocorticoids (6). Thus, we tested whether Cin B, Hpg, and Para would alter the repression of TNF-␣ target genes by GR.…”

Section: Activity Of Selected Gr Modulators In Cell-based Assays Of Gmentioning

confidence: 99%

“…This selectivity is based in part on tissue-specific factors and cross-talk pathways (5). For example, GR reduces the expression of certain inflammatory cytokines by inhibiting other transcription factors such as AP-1 and NF-b (6). Conversely, GR increases expression of RANKL, a gene coregulated by the vitamin D receptor that activates bone resorption by osteoclasts (7).…”

mentioning

confidence: 99%

Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening

Gerber

Masuno²,

Diamond

2009

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids are widely used to suppress inflammation and treat various immune-mediated diseases. Some glucocorticoid receptor (GR)-regulated genes mediate the therapeutic response, whereas others cause debilitating side effects. To discover selective modulators of the GR response, we developed a high-throughput, multiplexed system to monitor regulation of 4 promoters simultaneously. An initial screen of 1,040 natural products and Food and Drug Administration-approved drugs identified modulators that caused GR to regulate only a subset of its target promoters. Some compounds selectively inhibited GR-mediated gene activation without altering the repression of cytokine expression by GR. This approach will facilitate identification of genes and small molecules that augment beneficial effects of GR and diminish deleterious ones. Our results have important implications for the development of GR modulators and the identification of cross-talk pathways that control selective GR gene regulation.fluorescent protein ͉ high-throughput screen ͉ inhibitor ͉ selective modulator ͉ combinatorial therapy

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Mechanisms of glucocorticoid receptor signaling during inflammation

Cited by 358 publications

References 73 publications

Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening

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