Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme.

Abstract

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 2-to 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 investi...

Ventromedial hypothalamus lesions induce jejunal epithelial cell hyperplasia through an increase in gene expression of cyclooxygenase

“…There is other possibility that the production of PGs is enhanced by increased COX-1 level mediated through some other growth factors, for example, interleukins or glucocorticoid. 47,48 In conclusion, we demonstrated that VMH lesioning induced intestinal cell hyperplasia but not hypertrophy, resulting in the enlargement of villi height. We also demonstrated that the gene expression of COX-1 in the intestine was enhanced in VMH-lesioned rats.…”

Contribution of interleukin‐1β to the inflammation‐induced increase in nerve growth factor levels and inflammatory hyperalgesia

“…Inflammation results in an upregulation of the inducible COX-2 isoform of cyclo-oxygenase (Vane et al, 1994) which is readily induced by cytokines including IL-I (Maier et al, 1990). Indomethacin is relatively specific for COX-1 (Mitchell et al, 1993) while dexamethasone would be expected to prevent the protein synthesis-dependent induction of COX-2 during inflammation (Masferrer et al, 1992;Vane et al, 1994). In other words we should have blocked both the inducible and the constitutive forms of COX with the two treatments but failed in either case to modify substantially behavioural hypersensitivity, at least compared to anti-NGF.…”

Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock

“…These results reinforce the contribution made by mechanisms independent of NOS induction to the vascular hyporeactivity to NA. For instance, LPS induces an isoform of cyclo-oxygenase (COX-2) resulting in an enhanced formation of cyclo-oxygenase metabolites including vasodilator prostanoids (Masferrer et al, 1992). The subsequent enhanced formation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in the vascular smooth muscle and an impairment of the NA-mediated signal transduction (see Suba et al, 1992) (Szabo et al, 1993a).…”