Mechanism of action of glucocorticoids.
actions in this tissue. However, in other tissues glucocorticoids may exert their actions through mineralocor-ticoid receptors. Several actions of glucocorticoids that are too rapid to be explained by actions on transcription are mediated by effects on membrane receptors.
Because glucocorticoids regulate gene expression and protein synthesis, there is generally a lag of several hours before their effects are manifest. Moreover, the duration of various responses can endure after steroid levels fall. This may account for the fact that side effects elicited by steroids can be minimized by alternate-day therapy.
Metabolites of arachidonic acid, including prosta-glandins (PG), thromboxanes, and leukotrienes, are considered strong candidates as mediators of the inflammatory process. Steroids may exert a primary effect at the inflammatory site by inducing the synthesis of a group of proteins called lipocortins. These proteins suppress the activation of phospholipase A2, thereby decreasing the release of arachidonic acid and the production of proinflammatory eicosanoids (Fig. 60.6).
Another possible glucocorticoid-sensitive step is the PG endoperoxide H synthase (or cyclooxygenase) (COX) mediated conversion of arachidonate to PG endoperoxides (Fig. 60-6). The endoperoxides (PGG and PGH) are the precursors of PGE2, thromboxane A2 (TBXA2), and PGI 2, (prostacyclin). PG endoperoxide H synthase has two isoforms: one is constitutively expressed (PGHS-1, or COX-1), and another is induced by growth factors, cytokines, and endotoxins (PGHS-2, or COX-2). One component of the antiinflammatory action of glucocorticoids appears to involve the suppression of PGHS-2 induction in inflammatory cells by
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