Effect of Glucocorticoid Therapy on Glucocorticoid Receptors in Children with Autoimmune Diseases

Andreae, Judit; Tripmacher, Robert; Weltrich, Renita; Rohde, Wolfgang; Keitzer, R.; Wahn, Ulrich; Paul, K.; Buttgereit, Frank

doi:10.1203/00006450-200101000-00025

Cited by 30 publications

(29 citation statements)

References 44 publications

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“…The present study also found that the global methylation status of PBMCs in SLE patients was obviously lower than healthy controls, and it was related to the elevated GADD45α mRNA expression in SLE patients. Andreae et al [18] reported that the expression of GRα in PBMCs or renal biopsy tissues of patients with SLE was lower than that of healthy controls, and there was a negative correlation between GRα expression and disease activity. However, this article focused on protein levels not on mRNA.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of glucocorticoid receptor gene promoter results in glucocorticoid receptor gene low expression in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

et al. 2015

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Our aim was to investigate the relationship between the DNA methylation status of glucocorticoid receptor (GR) gene promoter and mRNA expression level of GRα gene of peripheral blood mononuclear cells (PBMCs) in patients with systemic lupus erythematosus (SLE). Fifteen newly emerging SLE patients and fifteen healthy controls were enrolled in this study. DNA and total RNA were extracted from the PBMCs of the SLE patients and healthy controls. The DNA methylation status of GR gene promoter 1 of PBMCs was detected through bisulfite-sequencing PCR. The mRNA expression of GRα, DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and growth arrest, and DNA damage-induced 45α (GADD45α) of PBMCs was detected using the quantitative real-time polymerase chain reaction method. The mRNA expression of GRα was significantly declined in SLE patients, and the mRNA expression of DNMT1 and GADD45α was significantly elevated in SLE patients. The global methylation status of PBMCs in SLE patients was obviously lower than healthy controls. There were 38, 25, 30, and 49 CpG islands in amplified fragment of GR promoter 1D, 1E, 1F, and 1H, respectively. The overall mean methylation status of the 152 CpG islands of the four promoters was significantly elevated in SLE patients. There was a negative correlation between hypermethylation of GR promoter and GRα mRNA expression in SLE patients. This study demonstrated that hypermethylation of GRα promoter may result in GRα gene low expression in PBMCs of patients with SLE. This study also found that the global methylation status of PBMCs in SLE patients was obviously lower than healthy controls, and it was related to the elevated GADD45α mRNA expression in SLE patients. These conclusions have to be certified by larger-scale clinical studies.

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Section: Discussionmentioning

confidence: 99%

Hypermethylation of glucocorticoid receptor gene promoter results in glucocorticoid receptor gene low expression in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

et al. 2015

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“…In contrast, other human-cell types, in which GCs do not induce apoptosis, are characterized by a down-regulation of the GR upon GC exposure. [6][7][8] Thus, up-regulation of the GR may be an important hallmark of ALL cells that normally undergo apoptosis upon GC exposure. We found that the three 3Ј GR splice variants GR-alpha, GR-beta, and GR-P were coordinately regulated over time.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 To induce apoptosis, GCs have to bind to the intracellular GC receptor (GR). Most cell types demonstrate a down-regulation of the amount of GR upon GC exposure, [6][7][8] probably as part of a physiologic feedback mechanism. 9 In contrast, an up-regulation of GR mRNA and protein levels has been demonstrated in various cell lines of lymphoid leukemias [10][11][12] and has been described as essential for GC-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL

Tissing

Meijerink

Brinkhof

et al. 2006

Blood

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Glucocorticoid (GC) resistance is an adverse prognostic factor in childhood acute lymphoblastic leukemia (ALL), but little is known about causes of GC resistance. Up-regulation of the glucocorticoid receptor (GR) has been suggested as an essential step to the induction of apoptosis in leukemic cells. In this study we investigated whether baseline mRNA expression levels of the 5 different GR promoter transcripts (1A1, 1A2, 1A3, 1B, and 1C) or differences in the degree of regulation of the GR or GR promoter transcripts upon GC exposure are related to GC resistance. Therefore, mRNA levels of the 5 GR promoter transcripts and of the GR were measured by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR; Taqman) technology in primary ALL cells prior to and after 3, 8, and 24 hours of prednisolone exposure. GR expression is induced upon GC exposure in primary ALL patient samples, which is opposite to what is found in tissues in which GCs do not induce apoptosis. GC resistance in childhood ALL cannot be attributed to an inability of resistant cells to up-regulate the expression of the GR upon GC exposure, nor to differences in GR promoter usage (at baseline and upon GC exposure). (Blood.

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“…The number of receptors varies in different organs and even within the same tissue [1,2]. Experimental and clinical studies indicate that the amount of GCR in cells changes in different pathological states [3,4,5,6,7]. In patients with asthma, a correlation between a lower number of receptors during GC therapy and response to treatment has been observed [4,8].…”

Section: Introductionmentioning

confidence: 99%

Expression of glucocorticoid receptors in mononuclear cells in nephrotic syndrome

Wasilewska

Zoch-Zwierz

Tomaszewska

et al. 2003

Pediatric Nephrology

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Coulter flow cytometry was used to determine glucocorticoid receptors (GCR) in the peripheral blood cells of patients with nephrotic syndrome. The expression of GCR in the lymphocytes (CD3/GCR) and monocytes (CD14/GCR) of peripheral blood of 23 (age 4.9+/-2.7 years) children with steroid-sensitive nephrotic syndrome was assessed before treatment (proteinuria >50 mg/kg per 24 h), after 4-6 weeks of prednisone treatment, without proteinuria, and in remission, without proteinuria and without any treatment. Before treatment the expression of CD3/GCR was 61.8+/-18.3% and CD14/GCR 43.6.8+/-20.3%; this did not differ from the results of the normal control group ( P>0.05). However, after treatment GCR expression in lymphocytes was 50% ( P<0.001) and in monocytes about 20% lower ( P<0.05). In remission, the GCR expression increased and did not differ from the results before treatment ( P>0.05). A positive correlation between the serum cortisol concentration and the expression of CD3/GCR was found ( r=0.504, P=0.02). In summary, we report that in children with steroid-sensitive nephrotic syndrome, prednisone treatment causes the temporary decrease of the expression of GCR in lymphocytes. A positive correlation between GCR expression and serum cortisol was found. A decrease in GCR expression in monocytes did not correlate with cortisol concentration.

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Effect of Glucocorticoid Therapy on Glucocorticoid Receptors in Children with Autoimmune Diseases

Cited by 30 publications

References 44 publications

Hypermethylation of glucocorticoid receptor gene promoter results in glucocorticoid receptor gene low expression in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

Hypermethylation of glucocorticoid receptor gene promoter results in glucocorticoid receptor gene low expression in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL

Expression of glucocorticoid receptors in mononuclear cells in nephrotic syndrome

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