A General Introduction to Glucocorticoid Biology

Abstract

Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results.

Keywords: SEDIGRAM; glucocorticoid receptor; glucocorticoids; inflammation; molecular biology.

Figure 1

Hypothalamic-pituitary-adrenal axis. The hypothalamic-pituitary-adrenal (HPA) axis activity is controlled by the circadian rhythm and can be induced by physiological and emotional stress. When activated, corticotrophin-releasing hormone (CRH), and arginine vasopressin (AVP) are released from the hypothalamic paraventricular nucleus (PVN). This induces the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland into the systemic circulation. ACTH will activate cortisol synthesis in the cortex of the adrenal gland. Cortisol negatively regulates the HPA-axis activity, e.g., by repressing the transcription of CRH and POMC by binding to negative glucocorticoid responsive elements (nGRE) or by binding to the transcription factor Nur77 involved in the POMC expression.

Figure 2

Conversion of inactive GCs to active GCs. Inactive Cortisone (human) and 11-dehydrocorticosterone (mouse) are activated to active cortisol and corticosterone by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), and inactivated again by 11β-HSD2.

Figure 3

Glucocorticoid receptor gene and protein. (A) Genomic structure of the glucocorticoid receptor (GR) gene. (B) Alternative splice and translation-initiation variants of the GR protein. (C) Structure of the GR protein consisting of an N-terminal domain (NTD), DNA-binding domain (DBD), a hinge region (H), and a ligand-binding domain (LBD), with a focus on the two zinc-fingers of the DBD and the GR^Dim mutation (A458T in human, A465T in mouse). Identified post-translational modifications of the GR are indicated in the black circles. Regions important in GR function are indicated below the protein. AF, Activation function; NES, Nuclear Export Signal; NLS, Nuclear Localization Signal; NRS, Nuclear Retention Signal; P, phosphorylation; S, sumoylation; U, ubiquitination; N, nitrosylation; O, oxidation; A, acetylation.

Figure 4

Glucocorticoid receptor chaperone complex and maturation. (A) After glucocorticoid receptor (GR) translation an Hsp70-Hsp40-GR complex is formed in the cytoplasm. (B) A subsequent ADP-dependent Hsp70 change induces the binding of Hop. (C) Hop induces the binding of Hsp90. (D) After Hsp90 binding to Hop, Hsp70, and Hsp40 are released from the chaperone complex and replaced by p23 and FKPB51. The GR has now matured into a high affinity complex. (E) After binding of glucocorticoids FKBP51 is replaced by FKBP52, which is necessary for the transport of the GR to the nucleus.

Figure 5

Glucocorticoid receptor activation and function. Lipophilic glucocorticoids (GCs) diffuse through the cell membrane and bind the glucocorticoid receptor (GR) in the cytoplasm. This induces a change in the chaperone complex bound to GR, after which it translocates to the nucleus to transactivate (+) or transrepress (-) gene transcription as a monomer or a dimer. The GR can transactivate genes by binding to glucocorticoid responsive elements (GRE) as a dimer, but also as a monomer by binding to other transcription factors (TF) through tethering or by binding to composite-elements. The GR can further transrepress gene-expression by binding to inverted repeat GR-binding sequences (IR-GBS), by tethering, by composite-elements, by competing for DNA binding-sites (BS), by sequestrating TFs and by competing for cofactors with other TFs. GR might also function as a tetramer, but its function is not known.

Figure 6

Sequence logo of the human glucocorticoid responsive element to which the GR binds to. See text for more details.

Figure 7

Overview of glucocorticoid-associated side effects.