Effect of Bacterial Endotoxin and Interleukin-1 on Prostaglandin Biosynthesis by the Hippocampus of Mouse Brain: Role of Interleukin-1 Receptors and Glucocorticoids

Abstract

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.

Astrocytes: new targets of melanocortin 4 receptor actions

“…Systemically administered a-MSH reduces cytokine expression in cerebral ischemia (Huang & Tatro 2002) and in brain inflammation induced by LPS (Rajora et al 1997). a-MSH was shown to inhibit PGE 2 release induced by LPS or IL1b from hippocampal fragments (Weidenfeld et al 1995) but not from hypothalamic fragments (Mirtella et al 1995). However, we reported that melanocortins inhibit the production of NO and PGs induced by IL1b in rat hypothalamus (Cragnolini et al 2006).…”

Alpha-Melanocyte-Stimulating Hormone through Melanocortin-4 Receptor Inhibits Nitric Oxide Synthase and Cyclooxygenase Expression in the Hypothalamus of Male Rats

“…α-MSH is a potent inhibitor of the induction of iNOS in cultured macrophages and NO production in liver and microglia [4, 17, 19]. Also, α-MSH was found to inhibit PGE 2 production in brain tissue [20, 21]. …”

Acute Effects of Purified and UV-Inactivated Herpes simplex Virus Type 1 on the Hypothalamo-Pituitary-Adrenocortical Axis

“…Since it has been shown that HPA axis responses to certain immune and stressful stimuli are inhibited in adrenalectomized (Adex) rats [11, 12], we examined whether circulating GC are required for the ACTH response to HSV-1 inoculation. Table 1 shows that in contrast to sham-operated rats, in Adex-rats HSV-1 inoculation did not cause an increase in serum ACTH levels above those found in vehicle-treated animals.…”