High Constitutive Glucocorticoid Receptor β in Human Neutrophils Enables Them to Reduce Their Spontaneous Rate of Cell Death in Response to Corticosteroids

Strickland, Ian; Kisich, Kevin O.; Hauk, Pia J.; Vottero, Alessandra; Chrousos, George P.; Klemm, Dwight J.; Leung, Donald Y.M.

doi:10.1084/jem.193.5.585

Cited by 204 publications

(174 citation statements)

References 28 publications

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“…Studies suggest that GCR␤, an alternative splice variant of the GCR which does not bind GC, antagonizes the transactivation activity of the classic GCR and may be implicated in GC resistance (65,66). The recent finding of GCR␤ in eosinophils from sinus biopsies of GC-resistant sinusitis patients (67) parallels the finding of GCR␤ in T cells from GC-resistant asthmatic patients (66), and GC-insensitive neutrophils (68). Whether GC-induced oxidant production, JNK activation, and mitochondrial injury will differ in eosinophils from GC-resistant subjects is the focus of ongoing research.…”

Section: Gm-csf Maintains Xiap Inhibits Both Prolonged Jnk Activatiosupporting

confidence: 56%

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

Gardai

Hoontrakoon

Goddard

et al. 2003

The Journal of Immunology

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The mainstay of asthma therapy, glucocorticosteroids (GCs) have among their therapeutic effects the inhibition of inflammatory cytokine production and induction of eosinophil apoptosis. In the absence of prosurvival cytokines (e.g., GM-CSF), eosinophils appear to be short-lived, undergoing apoptosis over 96 h in vitro. In a dose-dependent manner, GC further enhances apoptosis, while prosurvival cytokines inhibit apoptosis and antagonize the effect of GC. The mechanisms of eosinophil apoptosis, its enhancement by GC, and antagonism of GC by GM-CSF are not well-understood. As demonstrated in this study, baseline apoptosis of eosinophils resulted from oxidant-mediated mitochondrial injury that was significantly enhanced by GC. Mitochondrial injury was detected by early and progressive loss of mitochondrial membrane potential and the antioxidant protein, Mn superoxide dismutase (SOD). Also observed was the activation/translocation of the proapoptotic protein, Bax, to mitochondria. Underscoring the role of oxidants was the inhibition of mitochondrial changes and apoptosis with culture in hypoxia, or pretreatment with a flavoprotein inhibitor or a SOD mimic. GCs demonstrated early (40 min) and late (16 h) activation of proapoptotic c-Jun NH2-terminal kinase (JNK) and decreased the antiapoptotic protein X-linked inhibitor of apoptosis, a recently demonstrated inhibitor of JNK activation. Similarly, inhibition of JNK prevented GC-enhanced mitochondrial injury and apoptosis. Importantly, GM-CSF prevented GC-induced loss of X-linked inhibitor of apoptosis protein, late activation of JNK, and mitochondrial injury even in the face of unchanged oxidant production, loss of MnSOD, and early JNK activation. These data demonstrate that oxidant-induced mitochondrial injury is pivotal in eosinophil apoptosis, and is enhanced by GC-induced prolonged JNK activation that is in turn inhibited by GM-CSF.

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Section: Gm-csf Maintains Xiap Inhibits Both Prolonged Jnk Activatiosupporting

confidence: 56%

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

Gardai

Hoontrakoon

Goddard

et al. 2003

The Journal of Immunology

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“…We have demonstrated previously that IL-8 enhances GC insensitivity in neutrophils by increasing synthesis of GCR␤ relative to GCR␣ (10). Therefore, we performed Western analysis on extracts from neutrophils that had been treated with IL-8 as compared with unstimulated neutrophils (Fig.…”

Section: Sr Protein Levels In Neutrophils Stimulated With Il-8 -mentioning

confidence: 99%

“…For example, freshly isolated peripheral blood neutrophils are GC-insensitive. Both the absolute level of GCR␤ and the ratio of GCR␤ to GCR␣ protein are much higher in neutrophils than in peripheral blood mononuclear cells (PBMC) from the same individuals (10). The ratio of GCR␤ to GCR␣ can be altered by cytokine stimulation.…”

mentioning

confidence: 99%

Serine-Arginine-rich Protein p30 Directs Alternative Splicing of Glucocorticoid Receptor Pre-mRNA to Glucocorticoid Receptor β in Neutrophils

Leung

Kisich

2003

Journal of Biological Chemistry

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Glucocorticoid (GC) insensitivity is a major clinical challenge in the treatment of many inflammatory diseases. It has been shown previously that GC insensitivity, in several inflammatory cell types, is due to an overabundance of the ␤ isoform of the glucocorticoid receptor (GCR␤) relative to the ligand binding isoform, GCR␣. GCR␤ functions as a dominant inhibitor of GCR␣ action. A number of GCR isoforms are created from the same pre-mRNA transcript via alternative splicing, and the factor or factors that control alternative splicing of GCR pre-mRNA are of great importance. In the current study, we have identified the predominant alternative splicing factor present in human neutrophils, which is known to be exceptionally GC-insensitive. The predominant alternative splicing factor in neutrophils is SRp30c, which is one of several highly conserved serinearginine-rich (SR) proteins that are involved in both constitutive and alternative splicing in eukaryotic cells. Inhibition of SRp30c expression with antisense oligonucleotide strongly inhibited expression of GCR␤ and stimulated expression of GCR␣. Antisense molecules targeted to other SR proteins had no effect. Our data indicate that SRp30c is necessary for alternative splicing of the GCR pre-mRNA to create mRNA encoding GCR␤.Glucocorticoid (GC) 1 insensitivity is a major clinical challenge in the treatment of chronic inflammatory diseases. The pharmacologic actions of GCs are mediated through intracellular receptors, the glucocorticoid receptors (GCR). There are two isoforms of GCR in human cells, GCR␣ and GCR␤, which are generated from a single gene via alternative splicing of the primary RNA transcript. Several studies indicate that GC insensitivity has been associated with increased expression of GCR␤ (1-7). GCR␤ is truncated at the C terminus, which corresponds to the ligand binding domain. Thus, GCR␤ cannot bind GC. In addition, GCR␤ does not transactivate GC-sensitive genes and functions as a dominant inhibitor of GCR␣ (8). Previous studies suggest that GCR␣:GCR␤ heterodimer formation may account for the reduced effectiveness of GC action in cells overexpressing GCR␤ (8). Recent experiments in our lab demonstrated that overexpression of human GCR␤ by mouse hybridoma cells results in the development of GC insensitivity by these cells (9).Regulation of GCR␤ expression is not well understood. Different cell types from the same individual can have very different ratios of GCR␣ to GCR␤. For example, freshly isolated peripheral blood neutrophils are GC-insensitive. Both the absolute level of GCR␤ and the ratio of GCR␤ to GCR␣ protein are much higher in neutrophils than in peripheral blood mononuclear cells (PBMC) from the same individuals (10). The ratio of GCR␤ to GCR␣ can be altered by cytokine stimulation. After stimulation of neutrophils with IL-8, GCR␤ mRNA levels increased remarkably, and GCR␣ mRNA decreased to undetectable levels. Similarly, exposure of PBMC to IL-2 and IL-4 resulted in increased GCR␤ expression and development of steroid insensitivity (1,...

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“…Immune system homeostasis is balanced by GCs, which regulate immune cell turnover by suppressing cytokine production and promoting apoptosis. GC insensitivity due to elevated human GR␤ (hGR␤) expression results in higher levels of proinflammatory cytokines, leading to escalated cell growth and reduced cell death (16). As well, proinflammatory cytokines, such as tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1), increase expression of GR␤ via the NF-B pathway (17).…”

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confidence: 99%

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte

Wuescher

Marino

et al. 2014

Journal of Biological Chemistry

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Background:The glucocorticoid receptor ␤ (GR␤) is a positive regulator of growth. Results: GR␤ suppression of PTEN resulted in enhanced phosphorylation of Akt and growth. Conclusion: GR␤ enhances insulin-induced proliferation by suppressing PTEN and activating Akt1. Significance: GR␤ suppression of PTEN indicates that it has an important role in growth factor signaling and potentially cancer.

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High Constitutive Glucocorticoid Receptor β in Human Neutrophils Enables Them to Reduce Their Spontaneous Rate of Cell Death in Response to Corticosteroids

Cited by 204 publications

References 28 publications

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

Serine-Arginine-rich Protein p30 Directs Alternative Splicing of Glucocorticoid Receptor Pre-mRNA to Glucocorticoid Receptor β in Neutrophils

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

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