Differential effect of glucocorticoids on tumour necrosis factor production in mice: up-regulation by early pretreatment with dexamethasone

: Glucocorticoids (GC) are well known inhibitors of tumour necrosis factor (TNF) production. We investigated the role of endogenous GC in the regulation of TNF production in mice treated with lipopolysaccharide (LPS) using a pretreatment with dexamethasone (DEX) to down-regulate the hypothalamus-pituitary-adrenal axis (HPA). Short-term DEX pretreatment (up to 12 h before LPS) inhibited TNF production, but earlier (24-48 h) pretreatments potentiated it. This up-regulating effect was not observed in adrenalectomized mice or when GC synthesis was inhibited with cyanoketone (CK). This effect could not be explained only by the suppression of LPS-induced corticosterone (CS) levels induced by DEX, since a 48-h pretreatment potentiated TNF production without affecting LPS-induced CS levels. On the other hand, mice chronically pretreated with DEX were still responsive to its inhibitory effect on TNF production, thus ruling out the possibility of a decreased responsiveness to GC