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Corticosteroids have specific and nonspecific effects that are related to different mechanisms of action, including anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects. Most of their actions are mediated by an intracellular receptor called the glucocorticoid receptor. The glucocorticoid receptor α-isoform is located in the cytosol, binds glucocorticoids, and translocates to a region of the nuclear DNA known as the corticosteroid responsive element, where it is then able to stimulate or inhibit transcription of the adjacent genes, thus regulating the inflammatory process.1 The glucocorticoid receptor β-isoform does not bind glucocorticoids, but is able to bind the antiglucocorticoid/antiprogestin compound RU-486 to regulate gene expression.2 The glucocorticoid receptor β can attenuate the ligand-mediated transactivation of hormone-sensitive genes by the α-isoform and may be an important marker of steroid insensitivity.3
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Anti-Inflammatory Effects
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Corticosteroids are thought to exert their potent anti-inflammatory effects by inhibiting the release of phospholipase A2, an enzyme responsible for the formation of prostaglandins, leukotrienes, and other derivatives of the arachidonic acid pathway. Corticosteroids also inhibit transcription factors, such as activator protein 1 and nuclear factor κβ, which are involved in the activation of proinflammatory genes. Genes known to be upregulated by corticosteroids and that play a role in the resolution of inflammation include lipocortin and p11/calpactin-binding proteins, both involved in the release of arachidonic acid.1,4,5 Lipocortin I inhibits phospholipase A2, reducing the release of arachidonic acid from phospholipids.1,6,7 Corticosteroids also decrease the release of interleukin-1α (IL-1α), an important proinflammatory cytokine, from keratinocytes.1,8 Other proposed mechanisms for the anti-inflammatory effects of corticosteroids include inhibition of phagocytosis and stabilization of lysosomal membranes of phagocytizing cells.9
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Immunosuppressive Effects
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The effectiveness of corticosteroids is, in part, also due to their immunosuppressive properties. Corticosteroids suppress the production and effects of humoral factors involved in the inflammatory response, inhibit leukocyte migration to sites of inflammation, and interfere with the function of endothelial cells, granulocytes, mast cells, and fibroblasts.1,10–12 Several studies have shown that corticosteroids can cause mast cell depletion in the skin.13 Experiments have also shown that topical corticosteroids cause local inhibition of chemotaxis of neutrophils in vitro, and decrease the number of Ia+ Langerhans cells in vivo.14,15 Corticosteroids reduce eosinophilia in patients with asthma. They also reduce T-cell proliferation and induce T-cell apoptosis, in part from inhibition of the T-cell growth factor IL-2.1...