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    • It is increasingly argued that the

    2022-06-24

    It is increasingly argued that the immunosuppressive effects of GCs are conferred indirectly by GR through the activation of genes encoding proteins that inhibit IL-4, murine recombinant synthesis of proinflammatory genes 86, 87, 88. Genomic studies offer another mechanism compatible with the idea that GC-mediated repression is a secondary effect of GR function (Figure 2B). Treatment of mice with a GC drug caused liver gene expression changes that associated with a redistribution of GR and RNAPII from monomeric to dimeric GR-binding sites, with lost and gained sites enriched near repressed and induced genes, respectively [58]. This can be explained by expanding the classic squelching model to include the redistribution of TFs in addition to co-activators in response to external stimuli. Consistent with observations showing ligand-stimulated degradation of GR [89], the model proposes that both monomers and dimers are available in limiting amounts so that gain of occupancy at one set of sites leads to loss at another. Furthermore, by attributing GC-repressed transcription to the loss of activating GR monomers, the model maintains the logic of sequence-specific binding for GR genomic function. Given that squelching has been suggested to explain the transcriptional repression resulting from other NR ligands 90, 91, its role in NR function needs further examination.
    Concluding Remarks and Future Perspectives An overlooked area of inquiry from a genomics viewpoint is the potential interplay between GR and the MR. MR is unique among nuclear receptors because it can bind to multiple steroid hormones, including aldosterone, cortisol, and progesterone [92]. This is likely to have physiological consequences [93]. MR and GR bind with high affinities to cortisol, which circulates at concentrations that are 10–1000-fold higher than aldosterone, and HSD11B2 is absent in some tissues with high MR expression, such as myocardium and hippocampus. MR can form heterodimers with GR 94, 95, and with DNA-binding domains that share 94% similarity, and both receptors target the same DNA motif. Unfortunately, genomic data for MR are limited by the lack of good ChIP-grade antibodies, yet how and where it binds the genome may provide new mechanisms of GC signaling that could be leveraged for therapeutic gain.
    Acknowledgments We thank Hee-Woong Lim, Paul Titchenell, Matt Emmett, and Mitch Lazar for insightful comments, and Mary Leonard for figure artwork. We apologize to researchers whose relevant studies were not discussed because of space limitations. Research on GR in the laboratory of D.J.S. is supported by NIH grant R01 DK098542.
    Introduction Glucocorticoids, including cortisol and corticosterone, are secreted by the cortex of the adrenal gland [1,2]. These hormones are widely used as effective anti-inflammatory and immunosuppressive agents in the treatment of many autoimmune, allergic, and inflammatory diseases [3]. In teleosts, cortisol is the primary glucocorticoid in circulation and is produced by the interregnal cells of the head kidney in response to a stressor [4]. The neuroendocrine stress response in fish is mediated by the hypothalamic-pituitary-interrenal (HPI) axis, which is responsible for promoting the synthesis and secretion of cortisol [5,6]. The relationship between the immune system and HPI-axis indicates that hormones are important modulators of this system [7]. Cortisol action is mediated by two corticosteroid receptors (CRs), a glucocorticoid receptor (GR), and a mineralocorticoid receptor (MR); the GR is considered the primary receptor for cortisol action in teleosts [8]. GR is an important feedback regulator of the HPI axis and play a key role in mediating the stress effects of cortisol [6,9]. GR, a nuclear hormone receptor, belongs to the superfamily of ligand-activated transcription factors. Like other members of the family, GR possesses a modular structure consisting of three major domains: the N-terminal activation function-1 domain (AF-1), DNA binding domain (DBD), and a C-terminal ligand binding domain (LBD) [10]. GR signaling interacts with the immune system through two different mechanisms, namely genomic and non-genomic [11]. Upon ligand binding, the GR translocates into the nucleus, where it can regulate the expression of a diverse range of inflammatory and anti-inflammatory genes [12]. However, a recent study has shown non-genomic effects that are mainly mediated through glucocorticoid binding to plasma membrane GR (mGR), which subsequently activates kinase cascades in various tissues [13,14]. GR limits mortality and cytokine production by inducing anti-inflammatory genes [15] and protects macrophages in an LPS-induced shock model [14]. In monocytes, GR signaling is involved in the regulation of apoptosis, adhesion, chemotaxis, phagocytosis, and reactive oxygen metabolism, and can influence monocyte targeting to specific macrophage subpopulations [7,11]. In mice, it has been found that GR signaling in macrophages is involved in cell-and tissue-specific actions of glucocorticoids and plays a crucial role in tissue-repair mechanisms [16].