Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme ( prostaglandins / macrophages / steroids / eicosanoids )

The effect of endogenous glucocorticoids on the expression of the cyclooxygenase enzyme was studied by contrasting cyclooxygenase expression and prostanoid synthesis in adrenalectomized and sham-adrenalectomized mice with or without the concurrent administration of endotoxin. Peritoneal macrophages obtained from adrenalectomized mice showed a 2to 3-fold induction in cyclooxygenase synthesis and activity when compared to sham controls. Intravenous hj'ection of a sublethal dose of endotoxin (5 jzg/kg) further stimulated cyclooxygenase synthesis, resulting in a 4-fold increase in prostaglandin production. Similar cyclooxygenase induction can be achieved in macrophages obtained from normal mice but only after high doses of endotoxin (2.5 mg/kg) that are 100% lethal to adrenalectomized mice. Restoration of glucocorticoids in adrenalectomized animals with dexamethasone completely inhibited the elevated cyclooxygenase and protected these animals from endotoxin-induced death. In contrast, no signs of cyclooxygenase induction were observed in the kidneys of the adrenalectomized mice, even when treated with endotoxin. Dexamethasone did not affect the constitutive cyclooxygenase activity and prostaglandin production present in normal and adrenalectomized kidneys. These data indicate the existence of a constitutive cyclooxygenase that is normally present in most cells and tissues and is unaffected by steroids and of an inducible cyclooxygenase that is expressed only in the context of inflammation by proinflammatory cells, like macrophages, and that is under glucocorticoid regulation. Under normal physiological conditions glucocorticoids maintain tonic inhibition of inducible cyclooxygenase expression. Depletion of glucocorticoids or the presence of an inflammatory stimulus such as endotoxin causes rapid induction of this enzyme, resulting in an exacerbated inflammatory response that is often lethal. Prostaglandins and glucocorticoids are active endogenous participants in the inflammatory response. Endotoxin (lipopolysaccharide, LPS) administration to human volunteers increases the circulating levels of tumor necrosis factor (TNFa) and corticotropin (ACTH) and elicits hyperthermia. Cyclooxygenase (COX) inhibitors blunt the effect of LPS on body temperature and ACTH but not the rise in TNFa, implicating prostaglandins in some, but not all, of the symptoms associated with endotoxemia (1). Endogenous as well as exogenously administered glucocorticoids act to modulate the natural defense mechanisms that normally follow an inflammatory insult, thus preventing marked changes in homeostasis (2). Adrenalectomized (ADX) animals, which lack glucocorticoids, showed a more severe and often lethal inflammatory reaction to endotoxin (3, 4), which is prevented by the administration of the synthetic glucocorticoid dexamethasone (DEX) (5). Recent evidence suggests that the antiinflammatory effect of glucocorticoids involves inhibition of prostanoid synthesis (6, 7), possibly by the regulation of a cytokine-induced COX. Several investigators have shown that the glucocorticoid DEX inhibits the synthesis of COX in vitro in human dermal fibroblasts (8), differentiated U937 cells (9), blood monocytes (10), cultured vascular cells (11), and mouse peritoneal macrophages (12). Although early studies indicated that prostaglandin formation was not affected by glucocorticoid treatment (13, 14), recent work has shown that the in vivo administration of glucocorticoids to mice (15) and humans (16) inhibits eicosanoid synthesis. These results may be explained by suggesting the presence of a constitutive (unregulated) and an inducible COX that is regulated by steroids. Indeed, we have shown in vitro (8, 10, 12) and in vivo (15) that the inhibitory effect of glucocorticoids becomes effective only when the expression of the COX enzyme has been induced by proinflammatory agents such as interleukin 1 and LPS. Although the effect of glucocorticoids in pathological states is well established, the influence of endogenous steroids on basal or induced prostaglandin production in vivo has not been described. In this study, we utilize ADX mice with and without DEX supplementation to assess the role of endogenous glucocorticoids in the control of COX expression. Our results indicate that in the resident peritoneal macrophages, but not in the kidney, the expression of an inducible COX is regulated by endogenous glucocorticoid synthesis, implicating glucocorticoids in a selective tonic inhibitory action on prostanoid formation. When endogenous glucocorticoids are not present, as in the ADX animal, this enzyme becomes highly induced, resulting in an augmented output of prostanoids and an increased lethality.