Homeostatic Regulation of Glucocorticoid Receptor Activity by Hypoxia-Inducible Factor 1: From Physiology to Clinic

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.

Effects of Simvastatin on Cartilage Homeostasis in Steroid-Induced Osteonecrosis of Femoral Head by Inhibiting Glucocorticoid Receptor

“…Not only was the transcription level of HIF-1α decreased, but, also, the protein level of VHL significantly increased. The PHD3-VHL-E3 ubiquitin ligase complex was the main regulatory mechanism for the expression of the HIF pathway, and this complex strictly controlled the low level of HIF under normoxia [ 50 ]. The VHL was one of the core components, and the high level often represents the degradation of HIF-α.…”

Interaction of Vasopressin with Hormones of the Hypothalamo-Pituitary-Adrenal Axis: Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases

“…In various types of cells these factors may act either as co-activators or as co-repressors. Tissue-cell dependent expression of co-regulators causes specific tissue-cell action of steroid molecules [30,37,[48][49][50]. It is likely that the protein-protein interactions mediate rapid effects of steroid hormones and play essential role in trans-repression of genes by glucocorticoids in hypoxia and inflammatory processes.…”

“…It is likely that the protein-protein interactions mediate rapid effects of steroid hormones and play essential role in trans-repression of genes by glucocorticoids in hypoxia and inflammatory processes. For instance it has been found that they interact with hypoxia induced factors (HIFs) at the level of the promoter region of the inflammatory genes and can either enhance or inhibit activation of the HIF pathway [49,51]. It has been postulated that during the inflammatory processes the co-activating function of steroids determines collagen synthesis, generation of reactive oxygen species and engagement of peroxisome proliferator-receptor gamma co-activator 1-alpha (PGC-1α) as well as activation of p38 mitogen activated protein kinase (MAPK) and nicotinamide adenine dinucleotide phosphate oxidases (NOX) 2 and 4 [52,53].…”

“…It has been postulated that during the inflammatory processes the co-activating function of steroids determines collagen synthesis, generation of reactive oxygen species and engagement of peroxisome proliferator-receptor gamma co-activator 1-alpha (PGC-1α) as well as activation of p38 mitogen activated protein kinase (MAPK) and nicotinamide adenine dinucleotide phosphate oxidases (NOX) 2 and 4 [52,53]. On the other hand, glucocorticoids can inhibit inflammation through repression of genes engaged in synthesis of pro-inflammatory proteins (AP-1, NFκB) and through enhancement of expression of genes involved in generation of anti-inflammatory compounds [49,54].…”

Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research

“…A good case has been made for hypoxia-induced factors, or HIFs, a class of transcription factors that become active under conditions of reduced environmental oxygen availability, which may occur in inflamed tissues. In their review, Marchi et al [ 11 ] discuss extensive evidence for a complex cross-talk between HIFs and GR. In zebrafish and mouse studies, GR seems to potentiate HIF responses, while HIF activation suppresses both cortisol synthesis and redirects genomic GR responsiveness, effectively leading to curbed GR responses for many genes.…”