Abstract
Glucocorticoids (GCs) represent a well-known class of lipophilic steroid hormones biosynthesised, with a circadian rhythm, by the adrenal glands in humans and by the inter-renal tissue in teleost fish (e.g., zebrafish). GCs play a key role in the regulation of numerous physiological processes, including inflammation, glucose, lipid, protein metabolism and stress response. This is achieved through binding to their cognate receptor, GR, which functions as a ligand-activated transcription factor. Due to their potent anti-inflammatory and immune-suppressive action, synthetic GCs are broadly used for treating pathological disorders that are very often linked to hypoxia (e.g., rheumatoid arthritis, inflammatory, allergic, infectious, and autoimmune diseases, among others) as well as to prevent graft rejections and against immune system malignancies. However, due to the presence of adverse effects and GC resistance their therapeutic benefits are limited in patients chronically treated with steroids. For this reason, understanding how to fine-tune GR activity is crucial in the search for novel therapeutic strategies aimed at reducing GC-related side effects and effectively restoring homeostasis. Recent research has uncovered novel mechanisms that inhibit GR function, thereby causing glucocorticoid resistance, and has produced some surprising new findings. In this review we analyse these mechanisms and focus on the crosstalk between GR and HIF signalling. Indeed, its comprehension may provide new routes to develop novel therapeutic targets for effectively treating immune and inflammatory response and to simultaneously facilitate the development of innovative GCs with a better benefits-risk ratio.
Highlights
The name “glucocorticoid” (GC) is a portmanteau word, which derives from their key role in the regulation of glucose metabolism, their biosynthesis at the level of the adrenal cortex and their steroidal structure
In contrast to the previous observations, this study showed the presence of a clear dexamethasone-dose dependent inhibition of hypoxia-inducible factor transcription factors (HIF)-1α protein expression, which resulted in decreased HIF-1 target gene expression
In the last decades few in vitro studies have highlighted the potential for crosstalk between the hypoxia-inducible factor and glucocorticoid transcriptional responses
Summary
The name “glucocorticoid” (GC) is a portmanteau word (glucose + cortex + steroid), which derives from their key role in the regulation of glucose metabolism, their biosynthesis at the level of the adrenal cortex and their steroidal structure. To GCs that are involved in numerous homeostatic maintenance activities (e.g., metabolism of protein, carbohydrate and lipid, etc.) [64], the HIF signalling pathway exerts a pivotal role in ensuring homeostasis, the preservation of which is essential for the correct functioning of the cell In this regard, the ability to perceive and quickly respond to changes related to environmental oxygen availability is controlled by the hypoxia-inducible factor transcription factors (HIF) family. The primary effectors of the stress response are localized in the paraventricular nucleus (PVN) of the hypothalamus, in the anterior lobe of the pituitary gland and at the level of the adrenal gland These three main structures are generally referred to as the hypothalamic-pituitary-adrenal (HPA) axis in humans, and as the hypothalamic-pituitary-inter-renal axis (HPI) in zebrafish [62,92,93]. GCs may indirectly control the HPA axis activity through modulation of brain structures activity, such as the amygdala, the hippocampus and the prefrontal cortex, that can, in turn, influence the activity of the paraventricular nucleus [102,107,108,109]
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