Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform

Sousa, Ana R.; Lane, Stephen; Cidlowski, John A.; Staynov, D. Z.; Lee, Tak H.

doi:10.1067/mai.2000.106486

Cited by 249 publications

(164 citation statements)

References 20 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).…”

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

confidence: 92%

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 Activatiomentioning

confidence: 92%

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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“…1 In the brain, GR has a role in the negative feedback regulation of stress response 2 and modulates the transcription of genes required to equip the brain to respond to stress itself. 3 The complex actions of glucocorticoids (GCs) in specific tissues, 4 with age 5 and in disorders of GC resistance, 6 may be explained by the significant diversity of GR transcripts and isoforms ( Figure 1). This diversity includes 13 exon 1 mRNA variants 7,8 and 8 N-terminal variants, which arise from the predominant GR isoform, GRa, and differ in size from 94 to 54 kDa based on the location of their translation start site in exon 2 9 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…14 In contrast, the GRb and GRa-D 1À3 isoforms are present only in the nucleus 15 and may be involved in determining tissue-specific GC sensitivity. 6,11,16 GR has a critical role in normal human brain development 17 and controls the transcription of a range of genes critical to psychiatric health. Brainderived neurotrophic factor, for example, has been shown to be downregulated by GR [18][19][20] as well as in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development

et al. 2010

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The glucocorticoid receptor (GR) has a critical role in determining the brain's capacity to respond to stress, and has been implicated in the pathogenesis of psychiatric illness. We hypothesized that key changes in cortical GR occur during adolescence and young adulthood, at a time when individuals are at increased risk of developing schizophrenia, bipolar disorder and major depression. We investigated the mRNA and protein expression of GR in the dorsolateral prefrontal cortex across seven developmental time points from infancy to adulthood. GR mRNA expression, determined by microarray and quantitative real-time PCR, was lowest in neonates and peaked around young adulthood. Western blotting revealed two dynamic patterns of GRa protein expression across the lifespan, with N-terminal variants displaying differing unique patterns of abundance. GRa-A and a 67-kDa GRa isoform mirrored mRNA trends and peaked in toddlers and late in adolescence, whereas a 40-kDa isoform, very likely a GRa-D variant, peaked in neonates and decreased across the lifespan. GRa protein was localized to pyramidal neurons throughout life and most strikingly in young adulthood, but to white matter astrocytes only in neonates and infants ( < 130 days). These results suggest that the neonatal and late adolescent periods represent critical windows of stress pathway development, and highlight the importance of white matter astrocytes and pyramidal neurons, respectively, at these stages of cortical development. Evidence of dynamic patterns of GR isoform expression and cellular localization across development strengthens the hypothesis that windows of vulnerability to stress exist across human cortical development.

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“…[15][16][17] The GR has been the subject of intensive investigations, which aimed at identifying the cause of GC resistance. Studies with respect to receptor levels (sites/cell) in acute nonlymphoblastic leukaemia, 18 distribution of GR splice variants in asthmatic patients, 19 in chronic lymphocytic leukaemia 20 and in childhood ALL (own unpublished data, 2003), as well as studies in healthy subjects and childhood ALL patients investigating polymorphisms of genes known to be associated with drug resistance [21][22][23] all attributed to approach the cause of GC resistance. Furthermore, studies targeting the protein heterocomplex involved in the activation of the GR showed an association with GC resistance in human leukaemic cell lines and mouse fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia

et al. 2003

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Early reduction of leukaemic cells by chemotherapy is a strong predictor for treatment outcome in childhood acute lymphoblastic leukaemia (ALL). In ALL-(Berlin-Frankfurt-Mü nster) trials, early treatment response is assessed by the in vivo response to glucocorticoids (prednisone response, PR), the molecular background of which is unknown. The intracellular effects of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). In the absence of GC, the inactive GR resides within a multiprotein complex, consisting predominantly of the chaperone protein hsp90 (heat-shock protein 90). Until now, studies targeting GC resistance mainly focused on GR disorders and alterations of genes known to be associated with drug resistance. In addition, the GR multiprotein complex was associated with GC resistance in in vitro studies. We performed a case-control study for PR to investigate the association of in vivo GC resistance and hsp90 expression in childhood ALL. Hsp90 expression was assessed using a realtime PCR approach (Taqman technology) and Western blot technology. In this setting, we found no association of in vivo GC resistance and hsp90 expression. Therefore, we conclude that the expression of hsp90, the major component of the GR activating complex, is of minor importance for the in vivo GC resistance in childhood ALL.

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Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform

Cited by 249 publications

References 20 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

Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development

Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia

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