Mechanisms involved in tissue-specific apopotosis regulated by glucocorticoids

Rocha-Viegas, Luciana; Hoijman, Esteban; Beato, Miguel; Pecci, Adalı́

doi:10.1016/j.jsbmb.2008.03.007

Cited by 45 publications

(37 citation statements)

References 54 publications

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“…[35][36][37][38] The diverse roles of GRa on cell death and survival depend on differential modulation of pro-and antiapoptotic Bcl-2 family members. 39 As previously stated, the prosurvival effect of glucocorticoids is associated with increased expression of Bcl-X L , 17 the antiapoptotic molecule preferentially expressed by adult central and retinal neurons. 40 Evidence indicates that Bcl-X L blocks Bax translocation to the mitochondria 41 ; thus, we evaluated DEX and MFP effects on these two molecules.…”

Section: Figure 5 (A)mentioning

confidence: 86%

“…17,18 Glucocorticoid-dependent death or survival is directly associated with the selective expression of the short or long isoforms of Bcl-X (Bcl-X S or Bcl-X L ), which are pro-and antiapoptotic, respectively. 17 Cells resistant to glucocorticoid-induced apoptosis, such as some cancer cells 19,20 and fibroblasts, 21 show increased production of Bcl-X L . In the hippocampus, where they induce cell death, glucocorticoids increase the ratio of the proapoptotic molecule Bax relative to the antiapoptotic molecule Bcl-X L .…”

Section: Discussionmentioning

confidence: 99%

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Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Cubilla¹,

Bermúdez²,

Marquioni-Ramella³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, 60 lux/12 h dark).METHODS. Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor a (GRa) agonist, its antagonist mifepristone (MFP), or both drugs (DþM) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS.The antiapoptotic molecule Bcl-X L significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL þ nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (DþM). In the absence of MFP, DEX increased Bcl-X L in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL þ nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS.A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival. (Invest Ophthalmol Vis Sci. 2013;54:313-322)

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Section: Figure 5 (A)mentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Cubilla¹,

Bermúdez²,

Marquioni-Ramella³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Early discoveries include the induction by GR of NFKBIA (IkBa), an important inhibitor of NFKB-mediated inflammation (Auphan et al 1995;Scheinman et al 1995;Rhen and Cidlowski 2005), as well as GC-regulated genes involved in apoptosis (Viegas et al 2008), cell cycle progression (Rogatsky et al 1997), circadian rhythms (Balsalobre et al 2000), and intercellular signaling (Chinenov and Rogatsky 2007). Recently, hybridization to microarrays was used to identify 71 DEX-responsive genes, and chromatin immunoprecipitation (ChIP) followed by microarray hybridization (ChIP-array or ChIP-chip) experiments revealed that many of the genes exhibit GR:DNA binding near the transcription start site (TSS) (Wang et al 2004;So et al 2007).…”

Section: Sra008630]mentioning

confidence: 99%

Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation

Reddy

Pauli²,

Sprouse³

et al. 2009

Genome Res.

481

486

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The glucocorticoid steroid hormone cortisol is released by the adrenal glands in response to stress and serves as a messenger in circadian rhythms. Transcriptional responses to this hormonal signal are mediated by the glucocorticoid receptor (GR). We determined GR binding throughout the human genome by using chromatin immunoprecipitation followed by next-generation DNA sequencing, and measured related changes in gene expression with mRNA sequencing in response to the glucocorticoid dexamethasone (DEX). We identified 4392 genomic positions occupied by the GR and 234 genes with significant changes in expression in response to DEX. This genomic census revealed striking differences between gene activation and repression by the GR. While genes activated with DEX treatment have GR bound within a median distance of 11 kb from the transcriptional start site (TSS), the nearest GR binding for genes repressed with DEX treatment is a median of 146 kb from the TSS, suggesting that DEX-mediated repression occurs independently of promoter-proximal GR binding. In addition to the dramatic differences in proximity of GR binding, we found differences in the kinetics of gene expression response for induced and repressed genes, with repression occurring substantially after induction. We also found that the GR can respond to different levels of corticosteroids in a gene-specific manner. For example, low doses of DEX selectively induced PER1, a transcription factor involved in regulating circadian rhythms.

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“…2). The last appears to be quite reasonable, as glucocorticoids induce apoptosis in monocytes and macrophages, etc., but prevent apoptosis in other cells, such as fibroblasts [37]. …”

Section: The Inflamed Synovium - a Place For Two 11βhsdsmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

Schmidt

Straub

2014

Neuroimmunomodulation

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The tissue availability of active glucocorticoids (cortisol in humans) depends on their rate of synthesis from cholesterol, downstream metabolism, excretion and interconversion. The latter is mediated by the 11β-hydroxysteroid dehydrogenases (11βHSDs). In this review, we summarize the features of the two isoenzymes, 11βHSD1 and 11βHSD2, and current available experimental data related to 11βHSDs, which are relevant in the context of synovial cells in rheumatoid arthritis (RA). We conclude that due to complex feedback mechanisms inherent to the hypothalamic-pituitary-adrenal axis, currently available transgenic animal models cannot display the full potential otherwise inherent to the techniques. Studies with tissue explants, mixed synovial cell preparations, cell lines derived from synovial cells, and related primary cells or established cell lines indicate that there are relatively clear differences between the two isoenzymes. 11βHSD1 is expressed primarily in fibroblasts and osteoblasts, and may be responsible for fibroblast survival and aid in the resolution of inflammation, but it is also involved in bone damage. 11βHSD2 is expressed primarily in macrophages and lymphocytes, and may be responsible for their survival, suggesting that it is critical in chronic inflammation. The situation in synovial tissue would allow 11βHSD2-expressing cells to tap the energy resources of 11βHSD1-expressing cells. The overall properties of this local glucocorticoid interconversion system might limit therapeutic use of glucocorticoids in RA.

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Mechanisms involved in tissue-specific apopotosis regulated by glucocorticoids

Cited by 45 publications

References 54 publications

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation

11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

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