Glucocorticoid hormones and immune system

In 1950, the Nobel Prize for Physiology or Medicine was awarded to three scientists for the discovery of glucocorticoid hormones (GC), and their therapeutic values in the treatment of rheumatoid arthritis.

Synthesis
GC are a group of steroid hormones and are synthesized from cholesterol in the cortex of the adrenal gland. We and others have previously shown that GC can also be synthesized in the thymus with some paracrine effects on the development of T lymphocytes. Synthesis of GC is under the control of corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) produced by hypothalamus and pituitary gland respectively. On the other hand, high blood concentration of GC inhibits ACTH and CRH secretion, which leads to inhibition of GC production. Stressful conditions leads to elevation of blood GC concentrations. (Picture from thebrain.mcgill.ca).

Mechanism of action
GC diffuse through the cell membrane and binds to the glucocorticoid receptor (GR), which is a transcription factor expressed in almost all cell types. GR is sequestered in the cytoplasm. However, after binding to the GC, the hormone-receptor complex will translocate into the nucleus, where GR binds to its DNA response elements in the promoter region of target genes and by which modulates the gene transcription.

Immunological importance
GCs have wide spectrum of physiological effects involved in, for example, development, glucose metabolism and immune system. GC are well-known for their anti-inflammatory and immunosuppressive properties and thus have been widely used for the treatment of various autoimmune diseases, allergic reaction and also in transplantation. This is particularly the case when they are used at pharmacological doses. However, we and others have shown that GC at the physiological concentrations can also play important roles in the development and functions of immune system.

Glucocorticoids can inhibit expression of several genes involved in both cell-mediated and humoral immunity such as interleukin (IL)-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-12, IL-17, IFN gamma, FC receptors etc. These immunosuppressive actions of GC is known to be mainly via cross-talk between GR and other transcription factors such as nuclear factor-kappa B (NF-kappaB), which is a major transcription factor required for the expression of many molecules involved in different types of cell-mediated and humoral immunity. GC may also prevent the transcriptional activities of NF-kappaB by inducing the expression of I-KappaB alpha, which is the natural inhibitor of NF-kappaB.

Other important functions of GC are induction of apoptosis and inhibition of immune cell proliferation. This is particularly the case for T and B lymphocytes. These are the key mechanisms mediating the therapeutic effects of GC in the treatment of leukemias and lymphomas.