Dimitrios T. Boumpas, MD; George P. Chrousos, MD; Ronald L. Wilder, MD, PhD; Thomas R. Cupps, MD; James E. Balow, MD
Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid Therapy for Immune-Mediated Diseases: Basic and Clinical Correlates. Ann Intern Med. 1993;119:1198-1208. doi: 10.7326/0003-4819-119-12-199312150-00007
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Published: Ann Intern Med. 1993;119(12):1198-1208.
Glucocorticoids are pleiotropic hormones that at pharmacologic doses prevent or suppress inflammation and other immunologically mediated processes. At the molecular level, glucocorticoids form complexes with specific receptors that migrate to the nucleus where they interact with selective regulatory sites within DNA; this results in positive and negative modulation of several genes involved in inflammatory and immune responses. At the cellular level, glucocorticoids inhibit the access of leukocytes to inflammatory sites; interfere with the functions of leukocytes, endothelial cells, and fibroblasts; and suppress the production and the effects of humoral factors involved in the inflammatory response. Clinically, several modes of glucocorticoid administration are used, depending on the disease process, the organ involved, and the extent of involvement. High doses of daily glucocorticoids are usually required in patients with severe diseases involving major organs, whereas alternate-day regimens may be used in patients with less aggressive diseases. Intravenous glucocorticoids (pulse therapy) are frequently used to initiate therapy in patients with rapidly progressive, immunologically mediated diseases. The benefits of glucocorticoid therapy can easily be offset by severe side effects; even with the greatest care, side effects may occur. Moreover, for certain complications (for example, infection diathesis, peptic ulcer, osteoporosis, avascular necrosis, and atherosclerosis), other drug toxicities and pathogenic factors overlap with glucocorticoid effects. Minimizing the incidence and severity of glucocorticoid-related side effects requires carefully decreasing the dose; using adjunctive disease-modifying immunosuppressive and anti-inflammatory agents; and taking general preventive measures.
Steroid hormone (S) circulates as a free molecule or as a complex with plasma-binding protein. After the steroid enters the cell, it binds to receptors (R) that reside in the cytosol complexed to heat-shock protein (HSP) and immunophilin (IP). Binding of the ligand to the complex causes dissociation of HSP and IP. The receptor-ligand translocates into the nucleus where it binds at or near the 5-flanking DNA sequences of certain genes (glucocorticoid-responsive elements [GRE]). Receptor binding to the regulatory sequences of the responsive genes increases or decreases their expression. In the first instance (ON), glucocorticoids increase the transcription or stability or both of messenger RNA, which is translated on ribosomes to the designated protein. In the second instance (OFF), glucocorticoids repress (cross-hatched arrows) certain genes at the transcriptional level by interacting with and preventing the binding of nuclear factors required for activation of the gene (for example, activator protein [AP]-1 nuclear factor). In other instances, glucocorticoids exert their effects post-transcriptionally by either increasing the degradation of messenger RNA or by inhibiting the synthesis or secretion of the protein. The three main domains (immunogenic, DNA-binding, and ligand-binding) of the glucocorticoid receptor represented in a linear model. At left are the indicated domains and amino acid sequences of the receptor (see text for details). HSP 90 = heat-shock protein 90; NLS and NLS = nuclear localization sequences 1 and 2; and = transactivation domains 1 and 2.
Appendix Table 1.
The recruitment of leukocytes at sites of inflammation, their subsequent activation, and generation of secretory products contribute to tissue damage. Circulating leukocytes exit the vascular bed in response to chemotactic stimuli (for example, complement 5a [C5a], leukotrienes, interleukin-8 (IL-8), and transforming growth factor [TGF-]) released at sites of inflammation. The interaction of leukocytes with endothelial cells lining blood vessel walls represents the first critical step in leukocyte movement into the tissue. This is mediated by cell surface glycoproteins called adhesion molecules. The persistent migration and tissue accumulation of leukocytes to local inflammatory sites is paramount in initiating or modifying or both many disease processes .
Several adhesion molecules participate in the binding of leukocytes to endothelial cells . These molecules belong to at least three groups of glycoproteins: immunoglobulin supergene families, integrins, and selectins. Members of the immunoglobulin supergene family (intercellular cell adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) are found exclusively on the endothelial cells. Their counter-receptors on leukocytes belong to the integrin group of adhesion molecules (lymphocyte [leukocyte] function-associated antigen-1 (LFA-1), very late antigen-4 [VLA-4]). Members of the selectin group (endothelial leukocyte adhesion molecule-1 [ELAM-1], sialyl Lewis X) group can be found in both cell types. These adhesion molecules mediate the initial tethering and subsequent shear-resistant attachment of leukocytes to the endothelium as well as their penetration into the inflamed tissue. The cytokines interleukin-1, tumor necrosis factor-, and interferon- are also involved in this process through the activation of endothelial cells and the induction of adhesion molecules on their surface. Activated endothelial cells secrete interleukin-8 and other chemotactic cytokines that further stimulate the extravasation of leukocytes bound to endothelial cells.
Binding of antigen to the T-cell antigen receptor (TCR)-CD3 complex stimulates the tyrosine phosphorylation of several intracellular proteins. This is followed by activation of protein kinase C (PKC) and by an increase in intracellular calcium (Ca ) concentration, which then activates calcium-calmodulin-dependent kinases and phosphatases. The combination of these two signals (PKC and calcium) mediates the binding of nuclear proteins (transcription factors) to the interleukin (IL-2) gene promoter and initiates the transcription of the interleukin-2 gene. The newly synthesized interleukin-2 messenger RNA transcripts are transferred into the cytoplasm where they either are translated into the polyribosomes to the interkeukin-2 protein product (which is subsequently excreted) or are degraded by the RNAases. Glucocorticoids inhibit several steps during T-cell activation (indicated by the circled numbers). Thus, glucocorticoids inhibit the tyrosine phosphorylation (#1) but not the activation of PKC or the calcium . However, more distal sites in the calcium pathway (#2), such as the calcium-calmodulin kinase II, are inhibited . Binding of nuclear proteins (transcription factors) to the activated T cell (AT) (#3) and activator protein (AP)-1 (#4) sites of the human interleukin-2 promoter and its transcription activity are also inhibited by glucocorticoids . This results in decreased production of interleukin-2 messenger RNA. Glucocorticoids also increase messenger RNA degradation (#5) (probably through the induction of RNAases), resulting in a profound decrease in interleukin-2 messenger RNA accumulation in ribosomes (#6) and a decrease in translation into protein product (#7) . Inhibition of interleukin-2 production requires low doses of glucocorticoids, whereas higher doses are required to inhibit interleukin-2 gene transcription suggesting that post-transcriptional mechanisms are also important for the inhibition of interleukin-2 by glucocorticoids.
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