Nuclear binding of glucocorticoid receptors: Relations between cytosol binding, activation and the biological response

Bloom, Ernest; Matulich, Daniel T.; Lan, Nancy C.; Higgins, Stephen J.; Simons, S. Stoney; Baxter, John D.

doi:10.1016/0022-4731(80)90267-8

Cited by 96 publications

(17 citation statements)

References 32 publications

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“…1-4, Table 2) support the notion that glucocorticoids downregulate the levels of glucocorticoid receptor in HeLa S3 cells, we sought to substantiate these observations via a direct approach using [ 3 H]dexamethasone as described by Bloom et al (22). In Fig.…”

Section: Dexamethasone (M)mentioning

confidence: 53%

“…This notion may be related to the differences in the extent of down-regulation observed in the direct experiments and our Scatchard plot studies. The data in Table 2 show that down-regulation of glucocorticoid receptor by glucocorticoids is a time-dependent process that does not occur after 2 or 6 h of steroid treatment but is evident after 24 h. Bloom et al (22) have studied the influence of glucocorticoids on HTC cell glucocorticoid receptor. They showed no effect of preincubation on cellular receptor levels, but they examined the process for only 16 h. Perhaps the metabolism of receptor in HTC cells differs from HeLa S3, or perhaps their hormone treatment was not of sufficient duration.…”

Section: Discussionmentioning

confidence: 95%

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Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S₃Cells*

Cidlowski

1981

Endocrinology

186

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HeLa S3 cells contain high affinity, saturable receptors specific for glucocorticoids (congruent to 20,000 per cell). Growth of HeLa S3 cells in media containing dexamethasone (10(-6) M) results in a pronounced (congruent to 70%) reduction in the total cellular level of nuclear or cytoplasmic dexamethasone receptor number without any alteration in steroid-receptor dissociation constant (Kd congruent to 1 X 10(-9) M). This reduction in receptor number is not the result of simple receptor occupation, since this effect also occurs when receptor number is modulated by the direct addition of [3H]dexamethasone. Both control and dexamethasone-treated cells attain equilibrium states of receptor binding by 120 min at 0 C and by 60 min at 37 C, enabling estimation of receptor number and affinity by Scatchard analysis of saturation curves. Down-regulation of glucocorticoid receptor occurs at steroid concentrations as low as 10(-9) M (40% reduction). This alteration in receptor occurs after 24 h of hormone but not after either 2 or 6 h. Only the active glucocorticoids, (dexamethasone, cortisol) down-regulate glucocorticoid receptors. Cortexolone, estradiol, and 5 alpha-dihydrotestosterone have no apparent effect on this process, whereas progesterone (10(-7) M) is partially effective. Subcellular distribution studies indicate that glucocorticoids affect only that population of receptors capable of nuclear translocation at 37 C. We conclude that glucocorticoids can regulate the metabolism of their own receptors, via undefined mechanisms.

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Section: Dexamethasone (M)mentioning

confidence: 53%

Section: Discussionmentioning

confidence: 95%

Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S₃Cells*

Cidlowski

1981

Endocrinology

186

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“…The significant increase in the number of GcR following 24 h of IL-1b treatment (Figs 3 and 4) is in agreement with this hypothesis. Although it is not known whether the increase in GcR number would enhance glucocorticoid sensitivity, there is evidence of a direct relationship between the number of GcR and the biological activity of this receptor [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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SUMMARYEndotoxin or lipopolysaccharide (LPS) tolerance may be partially due to the secretion of potent antiinflammatory cytokines following severe Gram-negative infections, or by low doses of LPS. In this work, we describe the effects of interleukin-1b (IL-1b) and tumour necrosis factor alpha (TNF-a), two early cytokines secreted after LPS exposure, in the induction of LPS tolerance. Our results demonstrate that mice treated with three daily doses of 100 ng of IL-1b were tolerant to LPS-induced shock. However, TNF-a was unable to induce an LPS refractory state. Given the fact that 100 ng of IL-1b increase the plasma levels of glucocorticoids, we evaluated whether a daily injection of dexamethasone (DEX) alone was able to reproduce the LPS-like tolerant state. However, no signs of LPS refractoriness were detected, except when DEX was administered concomitantly with a dose of IL-1b that does not induce corticosterone secretion (12 ng/mouse). This dose was found to induce in vitro up-regulation of the glucocorticoid receptors (GcR) of peritoneal macrophages following 24 h of treatment. In addition, we demonstrate that IL-1b is capable of inducing the down-regulation of Toll-like receptor 4 (TLR4), a crucial molecule in the signal transduction of LPS. Taken together, our results indicate that IL-1b can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the downregulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects.

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“…Therefore, corticosteroid induced immunosuppression appears to constitutes a risk factor for the development of KS. The mechanism of corticosteroid action involves passive diffusion through the cell membrane, movement to the nucleus and regulation of the transcription of target genes 6 . Systemic corticosteroids are potent immunosuppressive and anti-inflammatory agents.…”

Section: Discussionmentioning

confidence: 99%

Kaposi Sarcoma after Corticosteroid Therapy for Idiopathic Thrombocytopenic Purpura

et al. 2009

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Nuclear binding of glucocorticoid receptors: Relations between cytosol binding, activation and the biological response

Cited by 96 publications

References 32 publications

Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S₃Cells*

Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S₃Cells*

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Kaposi Sarcoma after Corticosteroid Therapy for Idiopathic Thrombocytopenic Purpura

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Nuclear binding of glucocorticoid receptors: Relations between cytosol binding, activation and the biological response

Cited by 96 publications

References 32 publications

Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S3Cells*

Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S3Cells*

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Kaposi Sarcoma after Corticosteroid Therapy for Idiopathic Thrombocytopenic Purpura

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Product

Resources

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Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S₃Cells*

Regulation of Glucocorticoid Receptors by Glucocorticoids in Cultured HeLa S₃Cells*