title: PGE2 Inhibits IL-10 Production via EP2-Mediated β-Arrestin Signaling in Neuroinflammatory Condition.
abstract: Regulatory mechanisms of the expression of interleukin-10 (IL-10) in brain inflammatory conditions remain elusive. To address this issue, we used multiple primary brain cell cultures to study the expression of IL-10 in lipopolysaccharide (LPS)-elicited inflammatory conditions. In neuron-glia cultures, LPS triggered well-orchestrated expression of various immune factors in the following order: tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and lastly IL-10, and these inflammatory mediators were mainly produced from microglia. While exogenous application of individual earlier-released pro-inflammatory factors (e.g., TNF-α, IL-1β, or PGE2) failed to induce IL-10 expression, removal of LPS from the cultures showed the requirement of continuing presence of LPS for IL-10 expression. Interestingly, genetic disruption of tnf-α, its receptors tnf-r1/r2, and cox-2 and pharmacological inhibition of COX-2 activity enhanced LPS-induced IL-10 production in microglia, which suggests negative regulation of IL-10 induction by the earlier-released TNF-α and PGE2. Further studies showed that negative regulation of IL-10 production by TNF-α is mediated by PGE2. Mechanistic studies indicated that PGE2-elicited suppression of IL-10 induction was eliminated by genetic disruption of the PGE2 receptor EP2 and was mimicked by the specific agonist for the EP2, butaprost, but not agonists for the other three EP receptors. Inhibition of cAMP-dependent signal transduction failed to affect PGE2-mediated inhibition of IL-10 production, suggesting that a G protein-independent pathway was involved. Indeed, deficiency in β-arrestin-1 or β-arrestin-2 abolished PGE2-elicited suppression of IL-10 production. In conclusion, we have demonstrated that COX-2-derived PGE2 inhibits IL-10 expression in brain microglia through a novel EP2- and β-arrestin-dependent signaling pathway.
authors.affiliation: Neuropharmacology Section, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA.
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chu
authors.forename: Shih-Heng
authors.initials: SH
authors.lastname: Chen
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Langenbach
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Darryl
authors.initials: D
authors.lastname: Zeldin
authors.forename: Shiou-Lan
authors.initials: SL
authors.lastname: Chen
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Huiming
authors.initials: H
authors.lastname: Gao
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D058307:Receptors, Prostaglandin E, EP2 Subtype; D014409:Tumor Necrosis Factor-alpha; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016753:Interleukin-10; D051546:Cyclooxygenase 2; D015232:Dinoprostone