ReviewGlucocorticoid resistance in chronic diseases
Introduction
Glucocorticoids (GCs) are steroid hormones involved in several responses triggered by a variety of environmental and physiological stimuli. These hormones have wide-range regulatory effects on development, metabolism, and the immune system, and are synthesized and released into the circulatory system by the adrenal cortex through activation of the hypothalamus-pituitaryadrenal (HPA) axis. In stressful situations, the hypothalamus releases the corticotropin-releasing hormone that stimulates the release of the adrenocorticotropic hormone (ACTH). In response to ACTH, the adrenal cortex synthesizes and releases GCs. As part of a feedback response, elevated circulating GCs levels inhibit further ACTH release. Therefore, GCs constitute part of the adaptive stress response mechanism that maintains behavioral homeostasis.
Under stressful conditions, endogenous physiologically active cortisol is released in humans while corticosterone is released in rodents. These steroid hormones act through glucocorticoid receptors (GRs) or mineralocorticoid receptors (MRs). Through the activation of GRs, GCs regulate diverse cellular functions, including development, homeostasis, metabolism, cognition, and inflammation [1].
Chronic psychological stress is associated with high risks for depression, cardiovascular disease, diabetes, autoimmune diseases, upper respiratory infections, and poor healing [2]. Persistent exposure to environmental and psychological stress, concomitant with increased circulating GCs, is a probable risk factor for the current obesity and metabolic syndrome epidemics [3]. Indeed, organ transplant or chronic inflammatory-related illness patients chronically treated with exogenous GCs show features of metabolic syndrome. Over the last decades, these physiological hormones have been complemented by several synthetic GCs developed and provided by the pharmaceutical industry. While used for therapeutic purposes, these compounds are currently among the most commonly prescribed drugs worldwide.
The use of GCs is continuously growing as a result of increased chronic disease prevalence in the ageing segment of the population. Currently, GCs are used in the treatment of asthma, allergic rhinitis, hematologic malignancies, ulcerative colitis, rheumatoid arthritis, eczema, and psychological disorders. Although GCs are highly effective for therapeutic purposes, some patients chronically treated with GCs develop reduced GC sensitivity or resistance [4]. Alterations in the GR could also lead to GC resistance, thus increasing vulnerability to exaggerated inflammatory responses [5]. Specifically, several reports have detected GC resistance in chronic stress or major depressive disorder patients, as well as in elderly individuals and subjects at high risk for cardiovascular conditions [6]. Furthermore, GC resistance may occur as a result of prolonged exposure to inflammatory cytokines [6]. Importantly, synthetic GCs, such as dexamethasone or prednisolone, mainly act through GRs in contrast to cortisol or corticosterone. Therefore, the overall effects of chronic synthetic GC administration could differ from endogenous GCs, which act through both GRs and MRs.
Presently, the idea that the adverse effects of GCs are mainly due to increased circulating GCs levels is controversial, and there is greater focus on GR sensitivity as a highly relevant factor for the GCs response and effects of this process. To shed light onto this debated subject, it is crucial to understand how different tissues respond to GCs. In this review, we discuss the complexity of GR in the contexts of gene expression and regarding genomic and non-genomic actions. We also highlight the impacts of GCs resistance in chronic diseases.
Section snippets
Glucocorticoid receptors
Glucocorticoid actions are mainly mediated by two nuclear receptors, the GR and the mineralocorticoid receptor (MR). Both are members of the steroid/thyroid hormone receptor superfamily of ligand-inducible transcription factors, which include GCs, vitamin-D, and the thyroid receptor [7], [8], [9]. The human GR (hGR, NR3C1) is the product of a gene located in chromosome 5. While the hGR promoter lacks a consensus TATA box and CCAAT motif, it does contain binding sites for transcription factors
Genomic and non-genomic actions of glucocorticoids
Genomic GCs actions occur through a direct regulation of gene transactivation or transrepression. In the absence of a ligand, GRα mainly resides in the cytoplasm attached to a multisubunit complex that includes multiple molecular chaperones (Hsp90, Hsp70, and p23) and the immunophilins FKBP51 and FKBP52 [27]. These proteins maintain the receptor in a tridimensional structure that allows hormone binding and prevents unbound GR translocation into the nucleus, thereby preventing the modulation of
Primary generalized glucocorticoid resistance or Chrousos syndrome
Primary generalized glucocorticoid resistance, or Chrousos syndrome, is a familial disorder characterized by primary generalized tissue insensitivity to GCs. The first case of GC resistance in this syndrome was described in 1976 as hypercortisolism without the characteristics of Cushing’s syndrome, and the GCs resistance was related to impaired functioning of GRs [43]. To date, 20 hGR mutations have been described, with these mutations principally affecting ligand affinity, nuclear
Future perspectives and conclusions
Chronic diseases are the leading causes of global mortality, with incidences increasing with longevity. Chronic inflammation is a common condition in chronic diseases, including in type 2 diabetes, obesity, heart disease, cancer, and allergies. Abundant evidence supports that GC resistance occurs in several diseases that present a chronic inflammatory state (Table 1). Advances in understandings of GC signaling have identified a variety of cellular mechanisms that contribute to GR resistance,
Conflict of interests
The authors declare no conflict of interests regarding the publication of this paper.
Acknowledgements
Funding: This work was supported by the Comisión Nacional de Ciencia y Tecnología (CONICYT), Chile [FONDECYT 11130285 to R.T, 1130106 to M.LL., and FONDAP 15130011 to R.T.].
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