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

Abstract

Abstract:Brain inflammation includes microglial activation and enhanced production of diffusible chemical mediators, including prostaglandin E,. Prostaglandin E, 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 EP prevents microglial activation. In primary culture, microglial activation is predicted by a characteristic pattern of whole-cell potassium currents and interleukin-lp production. We investigated if prostaglandin E, 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 O-l 0 pM prostaglandin E2 and lipopolysaccharide for 24 h. Currents were elicited by using standard patchclamp technique, and interleukin-lp production was measured by ELISA. Peak outward current densities in microglia treated with lipopolysaccharide plus prostaglandin E, (10 nti) were reduced significantly from those of cells treated with lipopolysaccharide alone. Prostaglandin EP and 4-aminopyridine (a blocker of outward potassium currents) also significantly reduced interleukin-lp 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.

Interleukin-13 Enhances Cyclooxygenase-2 Expression in Activated Rat Brain Microglia: Implications for Death of Activated Microglia

“…In addition to 15d-PGJ 2 , anti-inflammatory roles of PGE 2 have been suggested. PGE 2 reduces the expression of inducible NO synthase (iNOS) and IL-1␤ (35,36). PGE 2 increases levels of anti-inflammatory lipid mediators, such as lipoxins (30,37).…”

The Action of Prostaglandins on Ion Channels

“…All these observations can be summarized by saying that PGE 2 concentrations between 1 and 10 M inhibit I K by 50% or less. Much greater PGE 2 sensitivity has been reported for the lipopolysaccharide-induced K + outward current in cultured rat microglia: 50% inhibition by 10 nM, 80% inhibition by 100 nM PGE 2 [17]. PGE 2 (100 nM) almost totally blocks the Ca 2+ -activated K + current which gives rise to a slow, Ca 2+ -dependent spike after-hyperpolarization in rabbit nodose neurons [118].…”

“…Also, the enhancement of the capsaicin-induced inward current by PGE 2 (see Fig. 4A) is mimicked by forskolin and completely blocked by intracellular perfusion of the PKA inhibitor PKI [14][15][16][17][18][19][20][21][22][23][24] [64]. Sensitization of mechanosensitive channels by PGE 2 is blocked by the PKA inhibitor H-89, an isoquinoline sulfonamide [20].…”

Prostaglandin E receptor 4 (PTGER4) involved in host protection against immune challenge in oyster, Crassostrea hongkongensis

“…It was shown that PGE2-PTGER4 signaling in mammalian macrophages suppressed the stimulus-induced expression of certain proinflammatory genes, including tumor necrosis factor (TNF)-a, interferon (IFN)-b and macrophage inflammatory protein (MIP)-1b [14,17]. Reportedly, in the setting of LPS stimulation, PGE2 signaling via PTGER4 decreased the levels of interleukin-1beta (IL-1b) [18] and inducible nitric oxide synthase (iNOS) [19] in microglia. Additionally, overexpression of PTGER4, as well as PTGER2, resulted in a significant reduction in the LPS-induced mRNA expression of proinflammatory chemokine monocyte chemotactic protein-1 (MCP-1) in glomerulonephritis [20].…”