Prostaglandin E2 and 4-Aminopyridine Prevent the Lipopolysaccharide-Induced Outwardly Rectifying Potassium Current and Interleukin-1β Production in Cultured Rat Microglia

Authors


Address correspondence and reprint requests to Dr. R. P. Kraig at Department of Neurology, MC2030, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, U.S.A.

Abstract

Abstract: Brain inflammation includes microglial activation and enhanced production of diffusible chemical mediators, including prostaglandin E2. Prostaglandin E2 is generally considered a proinflammatory molecule, but it also promotes neuronal survival and down-regulates some aspects of microglial activation. It remains unknown, however, if and how prostaglandin E2 prevents microglial activation. In primary culture, microglial activation is predicted by a characteristic pattern of whole-cell potassium currents and interleukin-1β production. We investigated if prostaglandin E2 could alter these currents and, if so, whether these currents are necessary for microglial activation. Microglia were isolated from mixed cell cultures prepared from neonatal rat brains and exposed to 0–10 µM prostaglandin E2 and lipopolysaccharide for 24 h. Currents were elicited by using standard patch-clamp technique, and interleukin-1β production was measured by ELISA. Peak outward current densities in microglia treated with lipopolysaccharide plus prostaglandin E2 (10 nM) were reduced significantly from those of cells treated with lipopolysaccharide alone. Prostaglandin E2 and 4-aminopyridine (a blocker of outward potassium currents) also significantly reduced interleukin-1β production. Thus, although prostaglandin E2 is classified generally as a proinflammatory chemical, it has complex roles in brain inflammation that include preventing microglial activation, perhaps by reducing the outward potassium current.

Abbreviations used: 4-AP, 4-aminopyridine; CR-3, complement type 3 receptor; DiI-Ac-LDL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-low-density lipoprotein; FBS, fetal bovine serum; IL, interleukin; K+ IR, inwardly rectifying K+ current; K+ OR, outwardly rectifying K+ current; LPS, lipopolysaccharide; NO, nitric oxide; PGB2, prostaglandin B2; PGE2, prostaglandin E2.

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