Mechanisms and clinical relevance of nongenomic glucocorticoid actions.

Glucocorticoids have profound anti-inflammatory and immunosuppressive actions when used therapeutically. The therapeutic dose is quite variable and depends on the disease, but ranges from very low to extremely high. The rationale for the use of various dosage regimens for specific clinical indications is the existence of three distinct, therapeutically relevant effects: genomic, specific nongenomic and unspecific nongenomic. Genomic effects are mediated by cytosolic receptors that alter expression of specific genes. Specific nongenomic effects occur within a few minutes and are mediated by steroid-selective membrane receptors. Unspecific nongenomic effects occur within seconds, but only at high glucocorticoid dosages, and seem to result from direct interactions with biological membranes. For unspecific nongenomic effects, methylprednisolone and other glucocorticoids have been shown to inhibit cation cycling across the plasma membrane, but to have little effect on protein synthesis. Thus, glucocorticoids could diminish or prevent the acute immune response by interfering with processes such as the rise in intracellular Ca2+ concentration. It is proposed that the additional therapeutic benefit of higher doses is obtained via these nongenomic effects.