Specificity and sensitivity of glucocorticoid signaling in health and disease

Cain, Derek W.; Cidlowski, John A.

doi:10.1016/j.beem.2015.04.007

Cited by 111 publications

(97 citation statements)

References 80 publications

(88 reference statements)

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“…Genomic effects of activated GRs occur after nuclear translocation and manifest through three primary mechanisms: direct binding of GR to DNA via GR response elements and negative GR response elements to activate or repress transcription; tethering to DNA-bound transcription factors to modulate transcription indirectly; or composite activity of DNA binding and interaction with adjacent DNA-bound transcription factors to affect transcription (39, 40). Rapid non-genomic effects of GR ligation occur after ligand-induced dissociation of the GR multiprotein complex in the cytoplasm (39). This diversity of regulatory processes indicates that prednisolone is likely to regulate different genes than the physiological glucocorticoid, hydrocortisone (41).…”

Section: Discussionmentioning

confidence: 99%

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

Quinkler¹,

Ekman

Marelli³

et al. 2017

Endocrine Connections

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Objective Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). Design/methods EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3–6 mg/day, n = 50) or hydrocortisone (15–30 mg/day, n = 909) were identified and grouped at a ratio of 1:3 (prednisolone:hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. Results Significantly higher mean ± s.d. total (6.3 ± 1.6 vs 5.4 ± 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 ± 1.4 vs 3.2 ± 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. Conclusions This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group.

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Section: Discussionmentioning

confidence: 99%

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

Quinkler¹,

Ekman

Marelli³

et al. 2017

Endocrine Connections

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“…“Non-genomic” effects are usually perceived as “non-classical”, since they have been relatively recently discovered, and are generally defined as transcription-independent effects. GCs are understood to mediate their classical genomic effects by binding to the cytoplasmic GR in target cells, resulting in the dissociation of inhibitory proteins, followed by dimerization, nuclear translocation and regulation of transcription of target genes in a cell- and gene-specific manner (Figure 1) (Baschant & Tuckermann, 2010; Busillo & Cidlowski, 2013; Cain & Cidlowski, 2015; Coutinho & Chapman, 2011; Dejager et al, 2014; Nicolaides et al, 2010; Oakley & Cidlowski, 2011; Van Bogaert et al, 2010). Whether the preformation of GR dimers is a prerequisite for DNA binding is controversial, with some reports suggesting it occurs on the DNA, after the two GR monomers bind DNA (Kleiman & Tuckermann, 2007; Nixon et al, 2013; Ong et al, 2010), while other reports suggest it occurs before DNA binding (Baschant & Tuckermann, 2010; Busillo & Cidlowski, 2013; Cain & Cidlowski, 2015; Coutinho & Chapman, 2011; Dejager et al, 2014; Nicolaides et al, 2010; Oakley & Cidlowski, 2011; Robertson et al, 2013; Van Bogaert et al, 2010).…”

Section: Brief Overview Of Mechanisms Of Gr Actionmentioning

confidence: 99%

Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy

Hapgood

Avenant

Moliki

2016

Pharmacology & Therapeutics

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Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC-resistance and severe side-effects, much research is focussed on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA-binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signalling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signalling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.

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“…The adrenal production of GCs is regulated by the hypothalamic-pituitary adrenal axis (HPA) in a circadian manner [10]. In response to a stressful stimulus, the hypothalamus releases corticotrophin-releasing hormone (CRH), which acts on the pituitary gland to stimulate the synthesis of adrenocorticotrophic hormone (ACTH) (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor signaling in the eye

2018

Self Cite

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Glucocorticoids (GCs) are essential steroid hormones that regulate numerous metabolic and homeostatic functions in almost all physiological systems. Synthetic glucocorticoids are among the most commonly prescribed drugs for the treatment of various conditions including autoimmune, allergic and inflammatory diseases. Glucocorticoids are mainly used for their potent anti-inflammatory and immunosuppressive activities mediated through signal transduction by their nuclear receptor, the glucocorticoid receptor (GR). Emerging evidence showing that diverse physiological and therapeutic actions of glucocorticoids are tissue-, cell-, and sex-specific, suggests more complex actions of glucocorticoids than previously anticipated. While several synthetic glucocorticoids are widely used in the ophthalmology clinic for the treatment of several ocular diseases, little is yet known about the mechanism of glucocorticoid signaling in different layers of the eye. GR has been shown to be expressed in different cell types of the eye such as cornea, lens, and retina, suggesting an important role of GR signaling in the physiology of these ocular tissues. In this review, we provide an update on the recent findings from in vitro and in vivo studies reported in the last 5 years that aims at understanding the role of GR signaling specifically in the eye. Advances in studying the physiological effects of glucocorticoid in the eye are vital for the elaboration of optimized and targeted GCs therapies with potent anti-inflammatory potential while minimizing adverse effects.

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Specificity and sensitivity of glucocorticoid signaling in health and disease

Cited by 111 publications

References 80 publications

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy

Glucocorticoid receptor signaling in the eye

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