Glucocorticoid-resistant bronchial asthma is characterized by failure of corticosteroids to suppress key asthma-relevant, cell-mediated inflammatory responses in the airways.
The mechanism of this phenomenon is not clear but may involve aberrant expression of the beta-isoform of the glucocorticoid receptor.
We have measured expression of the alpha- and beta-glucocorticoid receptor isoforms in tuberculin-driven cutaneous cell-mediated inflammatory lesions in people with asthma who are glucocorticoid sensitive and resistant after 9 days of therapy with oral prednisolone (40 mg/day) or matching placebo in a random order, crossover design.
After placebo therapy, the mean numbers of cells expressing glucocorticoid receptor alpha immunoreactivity in the lesions evoked in glucocorticoid-sensitive and -resistant patients with asthma were statistically equivalent. The numbers of cells expressing glucocorticoid receptor beta were significantly elevated in the patients who were glucocorticoid resistant, resulting in an 8-fold higher ratio of expression of glucocorticoid receptor alpha/glucocorticoid receptor beta in the patients who were glucocorticoid sensitive. Glucocorticoid receptor alpha/glucocorticoid receptors beta were colocalized to the same cells. Oral prednisolone therapy was associated with a significant decrease in the numbers of cells expressing glucocorticoid receptor alpha but not glucocorticoid receptor beta in the subjects who were glucocorticoid sensitive. No significant change was found in the numbers of cells expressing glucocorticoid receptor alpha and glucocorticoid receptor beta in the patients who were glucocorticoid resistant. Prednisolone therapy reduced the ratio of glucocorticoid receptor alpha/glucocorticoid receptor beta expression for the patients who were glucocorticoid sensitive to a level seen in the patients who were glucocorticoid resistant before therapy.
Because glucocorticoid receptor beta inhibits alpha-glucocorticoid receptor-mediated transactivation of target genes, the increased expression of glucocorticoid receptor beta in inflammatory cells might be a critical mechanism for conferring glucocorticoid resistance.
"GC actions are mediated through their cellular receptors. Because a dominant negative effect of GRβ was reported, a potential role for this receptor in GC-resistant states has been proposed [39-41,45]. Therefore our study evaluated the expression of GRα and β in septic patients. "
[Show abstract][Hide abstract] ABSTRACT: Background
A protective role for glucocorticoid therapy in animal models of sepsis was shown many decades ago. In human sepsis, there is new interest in glucocorticoid therapy at a physiological dose after reports of improved response to vasopressor drugs and decreased mortality in a selected group of patients. However, other reports have not confirmed these results. Cellular glucocorticoid resistance could explain a possible cause of that. To evaluate this hypothesis, we evaluated the expression of glucocorticoid receptor beta, the dominant negative isoform of glucocorticoid receptor, in peripheral mononuclear cells of septic patients and the effect of serum septic patients over glucocorticoid receptor expression and glucocorticoid sensitivity in immune cells culture.
A prospective cohort study and an in vitro experimental study with matched controls were developed. Nine patients with septic shock and nine healthy controls were prospectively enrolled. Mononuclear cells and serum samples were obtained from the patients with sepsis on admission to the Intensive Care Unit and on the day of discharge from hospital, and from healthy volunteers matched by age and sex with the patients. Glucocorticoid receptor alpha and beta expression from patients and from immune cell lines cultured in the presence of serum from septic patients were studied by western blot. Glucocorticoid sensitivity was studied in control mononuclear cells cultured in the presence of serum from normal or septic patients. A statistical analysis was performed using a Mann-Whitney test for non-parametric data and analysis of variance for multiple comparison; P < 0.05 was considered significant.
The patients' glucocorticoid receptor beta expression was significantly higher on admission than on discharge, whereas the alpha receptor was not significantly different. In vitro, septic serum induced increased expression of both receptors in T and B cells in culture, with a greater effect on receptor beta than the control serum. Septic serum induced glucocorticoid resistance in control mononuclear cells.
There is a transient increased expression of glucocorticoid receptor beta in mononuclear cells from septic patients. Serum from septic patients induces cell glucocorticoid resistance in vitro. Our findings support a possible cell glucocorticoid resistance in sepsis.
"The biological background of prednisone response is still unknown. However, there have been investigations with respect to glucocorticoid receptors , distribution of GR isoforms , and genetic polymorphisms . Polymorphisms at the promoter region of IL10 gene are associated with several diseases, including autoimmune, infectious, cancer, Alzheimer's disease (AD), and lymphoblastic leukemia . "
[Show abstract][Hide abstract] ABSTRACT: Interleukin 10 (IL10) is a pleiotropic cytokine that stimulates various hematopoietic cells. The tumor necrosis factor alpha (TNFα) is a cytokine that may influence the transcriptional activity induced by glucocorticoids. This study examined the impact of TNFα (G308A) and IL10 (G1082A) polymorphisms at promoter regions in relation to the overall survival of 105 children (0 ≤ 18 years) with acute lymphoblastic leukemia (ALL) for a period of 126 months, treated according to the protocol GBTLI99. The G1082A and G308A polymorphisms were identified by allele-specific PCR and PCR-RFLP, respectively. Patients with IL10AA genotype had a higher death ratio (44%, P = 0.0089). Patients with both IL10AA and TNFAA genotypes showed the worst survival when compared with the IL10GG and TNFGA genotypes (P = 0.0043). The results of this study revealed a lower survival among patients with IL10AA genotype and the concomitant occurrence of IL10AA and TNFAA genotypes.
"GRβ has been suggested to be upregulated in the steroid resistant asthmatics, and to be the most abundant GR isoform in neutrophils. GRβ was more highly expressed in glucocorticoid resistant asthmatics (Leung et al., 1997; Hamid et al., 1999; Sousa et al., 2000), although this is not a universal observation in glucocorticoid dependent (Gagliardo "
[Show abstract][Hide abstract] ABSTRACT: Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)beta, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRalpha. However, recent data suggest that GRbeta is not a dominant negative inhibitor of GRalpha in the transrepressive process and has its own functional role. We investigated the functional role of GRbeta expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-alpha-induced IL-8 release in an airway epithelial cell line. GRbeta expression was induced by treatment of epithelial cells with either dexamethasone or TNF-alpha. GRbeta was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-alpha-induced IL-8 transcription was not affected by GRbeta overexpression, rather GRbeta had its own weak suppressive activity on TNF-alpha-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRbeta overexpression, but TNF-alpha-induced histone H4 acetylation at the IL-8 promoter was decreased with GRbeta overexpression. This study suggests that GRbeta overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRbeta induces its own histone deacetylase activity around IL-8 promoter site.
Experimental and Molecular Medicine 04/2009; 41(5):297-306. DOI:10.3858/emm.2009.41.5.033 · 3.45 Impact Factor
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