Biphasic regulation by dexamethasone of IL-1-and LPS-stimulated endothelial prostacyclin production

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Abstract
Body reaction to injury comprises two major pathways: the immune response is predominantly mediated by IL-1 and other cytokines, and neuroendocrine mechanisms, resulting in increased glucocorticoid production. Each has distinct effects on prostaglandin (PG) production, which may in turn mediate both systemic and local inflammatory responses. The interactions if any, between the two systems on PG synthesis have not been studied. Bovine aortic endothelial cell cultures were used and prostacyclin (PGI2) production was monitored. Cells were treated with dexamethasone (Dex) 10−6 M and IL-1 10–30 U/ml in one experiment, and lipopolysaccharide (LPS, 0.1–1.0 μg/ml) in another experiment, separately or in combination, for either 2 or 24+2 h. While Dex was without effect, IL-1 and LPS stimulated PGI2 in a concentration and time dependent manner. Short exposure to Dex (2 h) enhanced the stimulation by IL-1 and LPS. On the contrary, more prolonged exposure (24+2 h) reversed the effects of IL-1 and LPS, resulting in PGI2 levels below baseline. A biphasic regulation by Dex was also observed with increasing concentrations of LPS. Dex was actually ineffective by itself, but it enhanced PGI2 production in combination with lower concentrations of LPS, while abolishing the influence of higher concentrations of this agonist. The data suggest that Dex may initially stimulate phospholipase A2 (PLA2) activity, while inhibiting it later. This biphasic behavior may be attributed to different concentrations of a PLA2-modulating protein, possibly lipocortin, that accumulate during exposure to Dex.