Ontogenesis of Glucocorticoid Receptors in Anterior Pituitary Gland: Transient Dissociation among Cytoplasmic Receptor Density, Nuclear Uptake, and Regulation of Corticotropic Activity*
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The present investigation was undertaken to define the developmental pattern of glucocorticoid binding to the anterior pituitary gland and ascertain whether that binding correlated to modulation of corticotropin-releasing factor-induced release of ACTH. Scatchard analysis of data revealed the presence in cytosol (besides classical receptor sites interacting with both [3H]dexamethasone and [3H]corticosterone) of a transcortin-like component binding only the natural steroid. Whereas the number of sites of the former binder was not significantly altered during maturation and remained close to the adult value (276± 12 fmol/mg protein), that of the latter declined dramatically after birth and rose again after postnatal day 10. The apparent Kd, however, remained unchanged. Transfer of the [3H]dexamethasone-receptor complex to nuclei of pituitary cells from neonates 2–6 days of age was found to be 20% that of adults despite the presence of comparable concentrations of receptor sites. Mixing experiments carried out with cytosol and nuclear fractions from different origins pointed to the cytoplasmic compartment as being implicated in this discrepancy. It was not until after postnatal day 10 that nuclear transfer reached mature levels. Although the extent of nuclear uptake and the magnitude of inhibition of ACTH secretion, as judged by means of a perifusion system, correlated well in hypophyses from 10- to 30-day-old neonates and adults, steroid binding and induction of biological response at earlier time points ere less closely related. The results indicate the existence during development of a transient dissociation between cytosol and nuclear binding of corticosteroids by the anterior pituitary as well as between the latter process and blockade of ACTH release. These data are discussed in connection with the postnatal period nonresponsive to stress. (Endocrinology108: 591, 1981)Cite
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Glucocorticoid exerts its anti-inflammatory effect mainly through the suppression of both AP-1 and NF-kappaB by its receptor, glucocorticoid receptor(GR). AP-1 and NF-kappaB are also supposed to be involved in glucocorticoid resistance. Here we describe the role of AP-1 and NF-kappaB in glucocorticoid resistance.
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Objective To investigate the relationship between sensitivity to glucocorticoid and glu- cocorticoid receptor(GR)isoforms in peripheral blood mononuclear cells(PBMC)isolated from patients with idiopathic thrombocytopenia purpura(ITP).Methods Real Time quantitative RT-PCR and immunocyto- chemical assay were used to measure the expression of and isoforms of glucocorticoid receptors(GRαand GRβ)in PBMC isolated from glucocorticoid-seasitive and resistant ITP patients as well as normal control groups.The expression of GRαand GRβat mRNA and protein level among these groups were further ana- lyzed and statistically compared.Results It was found that the mRNA level of GRβin PBMC isolated from glucocorticoid-resistant ITP patients was significantly higher than that from glucocorticoid-sensitive ITP pa- tients as well as coatrol groups(P0.01).Furthermore,the ratio of GRβ-positive PBMC was dramatically higher in glucocorticoid-resistant ITP group in comparison with that in glucocorticoid-sensitive and control groups(P0.01).However,the mRNA and protein level of GRαshowed little ditierence among these groups.Concldusion The response of ITP patieats to glucocorticoid treatment maybe closely associated with GRβexpression in their PBMC.
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On the basis of Scatchard and Lineweaver-Burk analysis, it was demonstrated that a series of drugs either activated or inhibited the function of types II and III glucocorticoid receptors. Analgine (0.04-10.0 mM) and sodium salicylate (12.5-50.0 mM) suppress the type II glucocorticoid receptor function of rat liver cytosol. Maradol (5.0 mM) increases the type II glucocorticoid receptors density but decreases the measurable constant for the [3H]acetonide triamsinolone interaction with type II glucocorticoid receptors. Analgine (1.25-10.0 mM) and sodium salicylate (0.62-10.0 mM) increase the type III glucocorticoid receptor function of rat liver cytosol. Maradol (0.25-1.0 mM) suppresses the type III glucocorticoid receptor function. The mechanism of regulation of the glucocorticoid effect by nonsteroid drugs influencing upon the function of types II and III glucocorticoid receptors is discussed.
Sodium salicylate
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The effect of corticosteroid therapy in COVID-19 patients is mediated by its suppressive effect on the regulations of inflammatory response. However, its clinical outcome is often unpredictable. This study aimed to explore the role of glucocorticoid receptors in corticosteroid response in Moderate-Severe COVID-19 patients. In this cross-sectional study, we attempted to find the relationship between the expression of the glucocorticoid receptor (encoded by NR3C1), the variation of glucocorticoid receptors isoform, and the mutations of glucocorticoid receptors exon with clinical response to corticosteroids. In addition, the relationship between glucocorticoid receptors expression and the expression of IκBα (encoded by NFKBIA) and glucocorticoid-induced leucine zipper protein (GILZ; encoded by TSC22D3) as steroid pathways was also evaluated. Thirty-four COVID-19 patients were studied. Blood was drawn before and on day 5 of corticosteroid treatment. Glucocorticoid receptors expression, isoform, and mutation were determined by RNA sequencing from white blood cells. Based on the improvement of clinical and oxygen status, patients were classified into responder and non-responder groups. Of thirty-four patients, 23 (67.6%) showed excellent responses to corticosteroids, and 11 (32.4%) were non-responders. The NR3C1 gene expression was significantly higher in the responsive group at baseline and after five days of glucocorticoid treatment. Isoform variant and mutation of glucocorticoid receptors did not correlate with clinical response. The expression of IκBα and GILZ correlated positively with glucocorticoid receptors expression. This study elucidates the relationship between glucocorticoid receptor expression with therapeutic responses to corticosteroids in moderate-severe COVID-19.
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Deacylcortivazol (DAC), a potent glucocorticoid, contains a phenyl-pyrazole moiety fused to the 2--3 position of the traditional steroid nucleus. When incubated with glucocorticoid-resistant mutants derived from the glucocorticoid-sensitive human leukemic cell line CEM-C7, DAC caused significant growth inhibition. However, this effect required 1 microM DAC, a concentration 50 times higher than that necessary for glucocorticoid receptor saturation. Cytotoxicity was observed in both mutants containing high-affinity glucocorticoid receptors defective in nuclear translocation and a mutant completely devoid of receptors. Further, in dexamethasone-resistant clones, DAC elicited only marginal increases in the activity of the glucocorticoid-inducible enzyme glutamine synthetase. Clones resistant to high concentrations of DAC could not be directly isolated from CEM-C7. However, stable DAC-resistant clones could be isolated from dexamethasone-resistant subclones of CEM-C7 with a frequency of 1 to 8 x 10(-4). These data are consistent with resistance to DAC being acquired in a two-step process. Our results suggest that the cytotoxicity of DAC at concentrations higher than necessary for glucocorticoid receptor saturation is not mediated by glucocorticoid receptors. Thus, DAC may be a bifunctional compound having both steroid receptor-mediated and receptor-independent cytotoxicity.
Antiglucocorticoid
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The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.
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Purpose of review Glucocorticoid action in development is of special interest not just in understanding how tissues and organs mature but also because altered developmental glucocorticoid levels can have lifelong effects on physiology, with overexposure predisposing to adult disease. However, in defined situations antenatal glucocorticoid treatment can have very beneficial therapeutic effects, especially accelerating fetal organ lung maturity in threatened premature birth. Recent findings Full glucocorticoid sensitivity requires expression of receptors (glucocorticoid receptor and mineralocorticoid receptor). Tissue glucocorticoid levels derive from the output of both maternal and fetal adrenal glands and glucocorticoid metabolism in the placenta and fetal tissues. Two 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes show tissue-specific expression of glucocorticoid-inactivating (11β-HSD2) or glucocorticoid-reactivating (11β-HSD1) activity and so have important influence on tissue availability of active glucocorticoid. By mapping out the gene expression of these receptors and 11β-HSD enzymes, a highly regulated pattern of changes is revealed, indicating prominent tissue and gestational-age-specific changes in determinants of glucocorticoid sensitivity. Responses of developing tissues to glucocorticoids are far from fully understood, but evidence supports such variations in sensitivity. Summary This review focuses on three organs, illustrating how glucocorticoids may influence the developmental program running in mammalian organs which at key points may be highly glucocorticoid sensitive and at others glucocorticoid effects may no longer be reversible and so permanently program changes in tissue function. The specific circumstances and pathways by which glucocorticoids have long-lasting beneficial and harmful actions are not yet known, but intelligent studies modeling these matters in animals provide a way forward.
Mineralocorticoid
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Glucocorticoid binding to cytoplasmic and nuclear fractions and gluco-corticoid-receptor complex binding to the nuclear fraction were investigated using rat liver. The glucocorticoid-receptor complex binding to the nuclear fraction was temperature-dependent, saturable, small in amount and of high affinity. The affinity and number of the glucocorticoid-receptor complex binding to the nuclear fraction were altered according to the glucocorticoid. Both the Bmax of nuclear glucocorticoid-receptor complex binding and the affinity of glucocorticoid to the cytoplasmic fraction were correlated with the relative anti-inflammatory potencies of glucocorticoids reported by Hynes and Murad (1980) and Fried et al. (1958). These results suggest that the number of nuclear binding sites of the glucocorticoid-receptor complex depends on the ligand steroid which is bound to the receptor of the cytoplasmic fraction and may be involved in physiological and pharmacological potencies of the glucocorticoid in addition to the affinity of the glucocorticoid to the receptor.
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