Glucocorticoids: exemplars of multi-tasking

Abstract

Well over 80 years ago Philip Smith described the beneficial clinical effects of adrenocortical extracts in animal models of adrenal insufficiency. In the ensuing years, scientists across the globe have sought to understand the mechanisms by which adrenal hormones and their synthetic analogues produce their complex and varied actions. Particular attention has focused on the glucocorticoids, partly because they have a vital place in the treatment of inflammatory and autoimmune disorders but also because dysregulation of the secretion and/or activity of endogenous glucocorticoids is increasingly implicated in a number of common disorders that pose a growing clinical burden, such as obesity, type II diabetes, the metabolic syndrome, hypertension and depression. This review considers some of the key advances that have been made in our understanding of the physiology, pathology and pharmacology of the glucocorticoids. Emphasis is placed on the molecular mechanisms of glucocorticoid signalling and the complex mechanisms that regulate the access of steroids in the systemic circulation to their receptors in their various target cells and tissues. In addition, consideration is given to the irreversible 'organisational' actions of glucocorticoids in perinatal life and to the potential role of the steroids in the aetiology of disease.

Figure 1

Diagram showing the hypothalamo-pituitary-adrenocortical (HPA) axis and principal loci of glucocorticoid feedback control. CRH=corticotrophin-releasing hormone; AVP=arginine vasopressin; and ACTH=adrenocorticotrophin hormone. Note that the intrahypothalamic parvocellular, CRH/AVP-secreting neurones originate in the paraventricular nucleus (PVN) and project to the median eminence where they terminate in close apposition to a capillary plexus (the primary plexus). CRH and AVP are secreted directly into these vessels and transported via the hypothalamo-hypophyseal portal system to the corticotrophs in the anterior pituitary gland. The CRH/AVP neurones are innervated by ascending nervous pathways from the brain-stem nuclei and by descending pathways from the limbic system and other centres (e.g. cortex). Circadian regulation is effected mainly via intrahypothalamic pathways from the suprachiasmatic nucleus (not shown). Local factors derived from glial cells (e.g. cytokines) and humoral factors (e.g. glucose) may also modulate the secretion of CRH/AVP. Similarly, locally produced substances also modulate the secretion of ACTH and glucocorticoids. Note (a) the concentration of AVP is considerably higher in hypothalamo-hypophyseal portal blood than in the systemic circulation; (b) vasopressin in the systemic circulation is derived from magnocellular neurones (not shown), which project from the PVN and supraoptic nuclei to the posterior pituitary gland.

Figure 2

Diagram illustrating (a) the amplification of glucocorticoid action in GR-expressing cells by type 1 11β-hydroxysteroid dehydrogenase (11β-HSD1), which acts as a reductase and reactivates cortisone and (b) protection of mineralocorticoid receptors (MRs) by type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2), which inactivates cortisol. Note that the reductase activity of 11β-HSD1 is dependent on the local generation of NADP(H) by hexose-6-phosphate dehydrogenase (H6PD). In rodents, 11β-HSD1 and 11β-HSD2 catalyse the interconversion of corticosterone and 11-deoxycorticosterone.

Figure 3

The five main domains of the GR, with some detail of the C-domain. The N-terminal A/B-domains include activational function domain 1 (AF-1), which facilitates transcriptional activity. The C-domain includes two cysteine-rich Zn²⁺ fingers and is responsible for receptor dimerisation and DNA binding. The D-domain or hinge region aids nuclear translocation as also does the C-terminal E-domain. The E-domain is also responsible for ligand binding, includes a second activational function domain 2 (AF-2) and may also have the ability to silence basal promoter activity. Mutations in the C-domain have given major insights into those facets of glucocorticoid action that are effected by receptor dimerisation and direct transcriptional regulation of the genome.

Figure 4

Phagocytic behaviour of leucocytes from ANXA1^−/− mice. (a) Phagocytosis of untreated (light shading) or opsonised (dark shading), zymosan by peritoneal macrophages from ANXA1^+/+, ANXA1^+/− and ANXA1^−/− mice. Pooled data from two experiments were analysed relative to ANXA1^+/+ controls, using two-tailed Student's t-test; n=6 per group. ^**P<0.01; ^***P<0.001, significantly different from Anx-1^+/+ opsonised values. ^††P<0.01 different from ANXA1^+/+ unopsonised values. (b) Inhibition by 10 μM hydrocortisone of IgG phagocytosis in peritoneal macrophages from different genotypes, using the RedOxyburst technique. Each experiment is typical of four similar experiments. White columns, % inhibition of reaction maximum; shaded columns, % inhibition of reaction rate. ^*P<0.05; relative to vehicle-treated controls. Inset: Typical trace showing inhibition of reaction by 10 μM hydrocortisone. Each point on the kinetic reaction plot above is the mean of three readings and the error bars represent standard errors of the mean. Reprinted from Hannon et al. (2003) with permission.

Figure 5

Expression of ANXA1 (annexin 1) in folliculostellate (FS) cells. (a) Electron micrograph from a freeze substituted mouse anterior pituitary section showing immunogold detection of ANXA1 in an FS cell adjacent to three endocrine (E) cells. Gold particles (15 nm) are scattered over the cytoplasm and adjacent to the plasma membrane of the cell; they are also localised on the FS cell surface at the ends of processes contacting endocrine cells (see enlarged inset). Arrows indicate intercellular junctions. Scale bar: 1 μm. (b) Immunofluorescence staining of ANXA1 in a murine follicuostellate (TtT/GF) cell line. Surface ANXA1 fluorescence (green) is evident on processes of TtT/GF cell (nucleic acids stained red with propidium iodide). Arrows indicate bright patches of cell surface ANXA1. Scale bars: 20 μm. Reprinted from Chapman et al. (2002) with permission.