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Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
National Center of Competence in Research ‘Kidney.CH’, Zurich, Switzerland
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Introduction Glucocorticoids, represented by cortisol in humans and corticosterone in rodents, play an essential role in several steps of adipocyte biology ( Peckett et al . 2011 ). During adipogenesis, glucocorticoids are required to induce
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rhythms are two of the most studied outputs of the circadian system in vertebrates. The dependence of melatonin, pituitary hormone and glucocorticoid rhythms on the LD cycle has been studied for decades in mammals ( Pevet & Challet 2011 , Kalsbeek et al
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-stimulating factors (G-CSF and GM-CSF), cytokines (interleukin (IL)-1β, IL-2, IL-6, IL-8 and tumor necrosis factor (TNF)-α), and glucocorticoids can delay apoptosis for up to 48 h in human and rodent neutrophils ( Cox 1995 , Liles et al. 1995 , 1996 , Meagher et
Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham, Birmingham, UK
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Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham, Birmingham, UK
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Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham, Birmingham, UK
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Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham, Birmingham, UK
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Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham, Birmingham, UK
School of Medicine, Worsley Building, University of Leeds, Leeds, UK
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Centre for Endocrinology Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham, Birmingham, UK
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Introduction The pathophysiological effects of glucocorticoids (GCs) are well described and impact upon almost all organ systems within the body. This is highlighted in patients with GC excess, Cushing’s syndrome, characterized by central
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Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed.
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Introduction Tissue-specific dysregulation of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in rodent ( Livingstone et al . 2000 , Liu et al . 2003 ) and human obesity ( Bujalska et al . 1997 , Fraser
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. 1990 ), has been attributed to several factors, including dietary modification ( Langley-Evans et al. 1994 , Woodall et al. 1996 ) and maternal stress during pregnancy ( Lesage et al. 2001 ). Excess exposure of the foetus to glucocorticoids may
Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Molecular Medicine Unit, CSB, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
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Introduction The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily. It is a key regulator of many homeostatic mechanisms and is also the target of therapeutic glucocorticoids used to treat inflammatory
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Glucocorticoids are critical for the physiological responses required to meet the metabolic demands of stressors. Chronic exposure to elevated levels of glucocorticoids, however, can have a negative physiological impact. For instance, chronic
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Introduction Glucocorticoids (GCs) are adrenal hormones involved in the stress response, regulating processes such as immune function and metabolism. The hypothalamus-pituitary-adrenal (HPA)-axis controls GC secretion via a cascade of hormonal
