Effect of Bacterial Endotoxin and Interleukin-1 on Prostaglandin Biosynthesis by the Hippocampus of Mouse Brain: Role of Interleukin-1 Receptors and Glucocorticoids
There is increasing evidence indicating that the production of cytokines and prostaglandins (PG) may be interrelated and is regulated by glucocorticoids (GC). In the present study we examined the effect of the bacterial endotoxin lipopolysaccharide (LPS) and interleukin-1 (IL-1) on the ex vivo production of PGE2 by the dorsal hippocampus of the mouse which contains high levels of receptors to IL-1. The roles of IL-1 receptors and GC in the regulation of LPS- or IL-1-induced PGE2 production were also studied. In control mice the basal rate of PGE2 ex vivo synthesis by slices of dorsal hippocampus was about 250 pg/mg protein/60 min. Intraperitoneal injection of either LPS (1-50 µg/mouse) or IL-1α (50-200 ng/mouse) increased the production of PGE2 in a dose- and time-dependent manner. Both LPS and IL-lα induced a maximal 2.5-fold increase in PGE2 production at 6 h after the injections. IL-1β was less effective by approximately 30% as compared to IL-1α. In mice treated with the IL-1 receptor antagonist or with the IL-1 antagonist α-melanocyte-stimulating hormone (α-MSH), the effects of LPS and IL-1 on PGE2 production were completely abolished. Intraperitoneal injections of dexamethasone (DEX) 5 or 30 µg/mouse 2 h prior to the administration of IL-1α significantly enhanced the effect of the cytokine on PGE2 production. In mice treated with 100 µg DEX/mouse, the facilitatory effect of the lower DEX doses in IL-1-induced PGE2 production was abolished. In adrenalectomized mice (6 days), the administration of IL-1 failed to affect hippocampal PGE2 production. Injection of DEX (30 µg/mouse) 18 and 2 h prior to IL-1α restored the effect of IL-lα on the production of PGE2. These results suggest: LPS and IL-1α or β can stimulate PGE2 biosynthesis by the mouse dorsal hippocampus; this effect is mediated by the specific IL-1 receptors and can be antagonized by α-MSH; in the mouse, GC may exert a permissive, a stimulatory or an inhibitory effect on IL-1-induced PGE2 hippocampal production. The relative intensity of each of these effects depend on the level of circulating GC.