The dosage of GCs used often increases based on clinical activity and severity of the RA.3,4 The rationale for this (mostly successful) clinical decision is: higher dosages increase GC receptor saturation in a dose-dependent manner, which intensifies the therapeutically relevant genomic GC actions; and it is assumed that with increasing dosages additional and qualitatively different nonspecific nongenomic actions of GCs increasingly come into play.
Genomic Actions of Glucocorticoids
The important anti-inflammatory and immunomodulatory effects of GCs are mediated predominantly by genomic mechanisms (Figure 10B-1). Binding to cytosolic GC receptors (cGCR) ultimately induces (“transactivation”) or inhibits (“transrepression”) the synthesis of regulator proteins.4 GCs influence the transcription of approximately 1% of the entire genome.5 The lipophilic structure and low molecular mass allow GCs to pass easily through the cell membrane and to form an activated GC/cGCR complex. This receptor complex is then translocated into the nucleus, where it binds as a homodimer to consensus palindromic DNA sites, which are called GC-responsive elements (GREs)].6 Depending on the target gene, transcription is either activated (transactivation via positive GRE) or inhibited (negative GRE). In addition to these mechanisms, the interaction of activated cGCR monomers with transcription factors such as AP-1 (activator protein-1), NF-kB (nuclear factor-kappaB), and NF-AT (nuclear factor for activated T cells) is recognized as a further important genomic mechanism of GC action.7,8 Accordingly, although the GC/cGCR complex does not inhibit their synthesis it modulates the activity of these factors–which leads to inhibition of nuclear translocation and/or function of these transcription factors and hence to inhibition of the expression of many immunoregulatory and inflammatory factors (transrepression). There are indications that many adverse clinical effects are caused by the transactivation mechanism (i.e., induced synthesis of regulator proteins), whereas many important anti-inflammatory effects are mediated by transrepression (i.e., inhibited synthesis of regulator proteins). This differential molecular regulation provides the basis for current drug-discovery programs that aim at the development of dissociating cGCR ligands. These novel substances, also called selective GC receptor agonists (SEGRAs), are being developed in order to obtain drugs with high repression activities against inflammatory mediator production but lower transactivation activities than traditional GCs. At the moment, it cannot be reliably predicted whether SEGRAs will as “improved GCs” enter clinical medicine in the near future.4,9,10
Nongenomic Actions of Glucocorticoids
Some regulatory effects of GCs arise within a few seconds or minutes. Such observations cannot be explained by the previously mentioned genomic actions because of the time these require. Nongenomic mechanisms of action are thought to be responsible for these rapid effects. Three different nongenomic mechanisms have been proposed to explain rapid anti-inflammatory and immunosuppressive GC effects: nonspecific interactions of glucocorticoids with cellular membranes,3,4 nongenomic effects that are mediated by the cGCR,11,12 and specific interactions with membrane-bound GCR.10,13–15
Glucocorticoid Effects on Immune Cells
Based on the mechanisms mentioned previoulsy, GCs mediate fascinating anti-inflammatory and immunomodulatory effects when used therapeutically. There are many specific effects of the commonly used GC drugs: virtually all primary and secondary immune cells are more or less affected. A selection of the most important effects on the different cell types is outlined in Figure 10B-2.16
Suppression of inflammatory and immune reactions and treatment of cancers of the lymphoid system are among the major applications of glucocorticoids. As noted above, despite early assumptions that such ‘pharmacological’ effects had no physiological basis, it is now clear that they are as physiological as are the effects on glucose metabolism. For example, induction of adrenal insufficiency in experimental animals (by adrenalectomy or administration of the glucocorticoid antagonist RU486) enhances inflammatory and immune reactions, showing that these reactions are physiologically regulated by endogenous glucocorticoids. Studies by Sternberg and coworkers also strongly suggest that dysregulation of the HPA axis can result in autoimmunity.
Anti-inflammatory and immunosuppressive actions of glucocorticoids are now known to be closely related, affecting nearly all cells that participate in immunity and inflammation and sharing fundamental cellular and molecular mechanisms that are under glucocorticoid influence. Glucocorticoids dramatically alter the distribution of leukocytes, markedly decreasing blood counts of lymphocytes, monocytes, eosinophils and basophils within 1–3 h of glucocorticoid administration. Recent work has shown that changes in blood leukocyte distribution result from glucocorticoid interaction with the type II adrenal steroid receptor. While neutrophil counts rise in the blood, glucocorticoids decrease the accumulation of leukocytes at inflammatory sites. Glucocorticoids also kill lymphocytes, largely by the initiation of apoptosis, a striking effect that is applied in the treatment of lymphocytic leukemias and lymphomas.
Numerous reactions that are fundamental to immunity – antigen-induced T and B cell proliferation, early B cell differentiation, antigen presentation, NK activity, differentiation and activation of macrophages – are suppressed by glucocorticoids. Although some of these are probably direct effects on the target cell being measured, others certainly involve indirect effects resulting from glucocorticoid regulation of intermediary molecules. In the past 20 years, the ability to glucocorticoids to inhibit the production of various inflammatory enzymes and cytokines, by mechanisms such as those outlined above, began to be recognized. Table 1 contains a partial list of mediators which are obligatory components of immune and inflammatory reactions and whose production is inhibited by glucocorticoids. Glucocorticoids also inhibit some effects of these mediators, such as responses of lymphocytes to IL-2 and of eosinophils to IL-3, IL-5, GM-CSF and IFNγ. By blocking communication via cytokines, glucocorticoids cut off signals required for clonal expansion and differentiation of antigen-specific T and B cells, as well as signals which activate effector functions that participate in inflammatory reactions. It seems likely, therefore, that a principal mechanism through which glucocorticoids control immune and inflammatory reactions is by suppressing cytokines and other mediators.
Table 1. Glucocorticoid regulation of mediators involved in immunity and inflammation
The complexity of the interplay between glucocorticoids and inflammatory mediators is evidenced by the increased expression of certain cytokine receptors in response to glucocorticoids, and probably by altered expression of glucocorticoid receptors induced by some cytokines. How might such effects fit with the models presented in Figures 3 and 4? Basal levels of glucocorticoid, and possibly the surge which occurs early in an immune response, may initially enhance the actions of cytokines by increasing expression of cytokine receptors. As cytokine concentrations rise, they act on the HPA to stimulate even higher levels of glucocorticoids which restrain further cytokine production unless very strong inflammatory signals persist. Normally, elimination of the antigen and resolution of the inflammation allows cytokine production to cease so that both cytokines and glucocorticoids return to basal levels. However, sustained inflammation with continued high levels of cytokines can persist in spite of high levels of glucocorticoid. This outcome might result in part from cytokine-induced reduction in glucocorticoid receptor expression, a mechanism postulated by some to contribute to steroid-resistant asthma.
GC elevations inhibit activity in PVN CRF cells and pituitary corticotropes, first by membrane GR-mediated effects, then by GC-associated GR protein–protein interactions altering gene expression. Feedback ensures controlled neuroendocrine responses. Longer term feedback effects exist in both brain and pituitary (e.g., through GC–GR complexes interacting with a negative GRE on POMC in corticotropes). Chronic GCs diminish HPA axis outflow in proportion to exposure, provided no concurrent stress exists, making the axis unresponsive to new stressors and thus explaining the requirement for extra GC coverage during major surgery in patients on chronic GC therapy.
There is rapid inhibitory GC feedback on both CRF and ACTH secretion. In hypothalamic slices in vitro, GC alters neuronal activity, including CRF-synthesizing cells, within 3 min. GC stimulates endocannabinoid secretion, presynaptically inhibiting glutamate-stimulated miniature excitatory postsynaptic currents (mEPSCs) via endocannabinoid EC-1 receptors. GCs infused directly into neurons does not have this effect, and rapid GCs actions on pituitary ACTH secretion in vitro are not inhibited by exposure to protein or by RNA synthesis inhibitors, suggesting membrane-mediated feedback.
Glucocorticoids (GCs) are a class of steroid hormones that have been known to be widely used clinically as antiinflammatory, immunosuppressive, antishock drugs. Unfortunately, they can also produce numerous and potentially serious adverse effects that limit their usage. Thus, it is necessary to search for novel GCs with a better benefit-risk ratio compared to conventional GCs. GCs are believed traditionally to take effects mainly via the so-called genomic mechanisms, which are also largely responsible for GCs’ side effects. However, an ever-growing body of evidence indicates that some effects of GCs can be mediated by the nongenomic mechanism. Theoretically, the discovery of nongenomic mechanisms of GCs provides novel approaches for the development of GCs to treat various diseases safely. The new GC drugs will take clinical effects mainly through the nongenomic mechanisms instead of classical genomic mechanisms to reduce side effects.
Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.
Glucocorticoid hormones have strong effects on memory and learning in most animals (Lupien and Lepage, 2001). Glucocorticoids are steroid hormones produced by the adrenal glands, and elevation in glucocorticoids is usually associated with stressful events. The most common glucocorticoid hormone in some mammals including humans is cortisol. Corticosterone, on the other hand, is the main glucocorticoid hormone in reptiles, birds, and other mammals (e.g., some rodents). Glucocorticoids (hereafter CORT) are essential hormones necessary for multiple physiological functions including regulation of metabolism and gluconeogenesis (e.g., Mizoguchi et al., 2004).
Glucocorticoids are often referred to as stress hormones because they are synthesized and secreted in response to pain and emotional trauma, caloric restriction, agonistic social encounters, and general anxiety. Mice homozygous for a null mutation in the GR (i.e., GR knockouts) die around the time of birth, indicating that the GR and glucocorticoids are essential for life.56 In humans, there are at least nine GR isoforms produced from a single gene. Whereas GRα and GRβ are produced by alternative splicing at the 3´ end of GR mRNA, GR-A, GR-B, GR-C1-3, and GR-D1-3 are produced by alternative translation initiation at the 5´ end of GR mRNA.57 Glucocorticoids alter the physiology of numerous tissues throughout the body during periods of acute stress. For example, the inhibitory effects of stress on reproduction are mediated by glucocorticoids at all levels of the hypothalamic–pituitary–gonadal axis. These hormones also influence brain function and behavior. Glucocorticoids mobilize energy stores by inducing the degradation of proteins to free amino acids in muscle, lipolysis in adipose tissue, and gluconeogenesis in the liver. Glucocorticoids play a role in the immune and vascular systems, where they induce programmed cell death in lymphocytes and block inflammatory responses. Although these changes are adaptive in the short term, chronic stress accompanied by prolonged glucocorticoid secretion is pathological.
In addition to mediating stress responses, glucocorticoids play an essential part in normal physiology. For example, glucocorticoids regulate the expression of numerous genes involved in energy homeostasis. The expression of phosphoenolpyruvate carboxykinase (PEPCK), is induced by glucocorticoids and is enhanced by the glucocorticoid-dependent increase in the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) in the liver.58,59 It has been reported that glucocorticoids also increase pyruvate dehydrogenase kinase 4 levels,60 which phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC). In turn, PDC inactivation promotes gluconeogenesis by conserving three-carbon substrates. Glucocorticoids regulate the expression of genes related to other physiological processes as well. For example, the well-known anti-inflammatory effects of glucocorticoids are mediated in part by induction of the gene for inhibitor of nuclear factor kappa B alpha (IκBα), which keeps the proinflammatory transcription factor nuclear factor kappa B (NF-κB) in an inactive state in the cytoplasm.
Glucocorticoids are primary stress hormones produced by the adrenal cortex. The concentration of serum glucocorticoids in the fetus is low throughout most of gestation but surge in the weeks prior to birth. While their most well-known function is to stimulate differentiation and functional development of the lungs, glucocorticoids also play crucial roles in the development of several other organ systems. Mothers at risk of preterm delivery are administered glucocorticoids to accelerate fetal lung development and prevent respiratory distress. Conversely, excessive glucocorticoid signaling is detrimental for fetal development; slowing fetal and placental growth and programming the individual for disease later in adult life. This review explores the mechanisms that control glucocorticoid signaling during pregnancy and provides an overview of the impact of glucocorticoid signaling on fetal development.
Glucocorticoids, with cortisol being the foremost player, comprehend a class of steroid hormones responsible for a wide range of actions. An important regulator in the glucocorticoid cascade is the glucocorticoid receptor. After binding of the glucocorticoid, this receptor can both up- and downregulate certain target genes but can also directly influence processes outside the nucleus. Since glucocorticoids possess the ability to effect nearly all bodily systems, genetic variations of the glucocorticoid receptor have been linked to alterations in body composition, cardiometabolic features, mental health, and response to treatment with exogenous glucocorticoids.
Glucocorticoids have both stimulatory and inhibitory effects on GH secretion, with the absolute effect depending on the timing and the glucocorticoid concentration. Glucocorticoid deficiency, as in Addision disease, leads to a decrease in GH secretion due to decreased expression of GHRH and GH secretagogue receptors.301 Acute exposure to supraphysiologic levels of glucocorticoids decreases GH secretion within 1 hour followed by a subsequent transient increase in GH secretion.301,302 Ongoing glucocorticoid excess then causes ongoing suppression of GH secretion. This decrease in GH secretion is due to an increase in somatostatin tone.301 Glucocorticoids can also impair growth through direct actions at the growth plate, by inhibiting local IGF-1 production through suppression of chondrocyte GHR expression, impairment of chondrocyte IGF-1 receptor expression,301,303 alterations in IGFBP levels, and impairment of intracellular signaling.304 Finally, glucocorticoids may stimulate apoptosis of growth plate chondrocytes.294
Additional indirect effects of excess glucocorticoids on growth can result from glucocorticoid inhibition of calcium absorption and reabsorption, with the development of secondary hyperparathyroidism.299 In pubertal children, glucocorticoid excess can induce sex hormone deficiency, causing a loss of the normal growth stimulatory effect of these hormones.299