Cyclooxygenase-1 mediates prostaglandin E2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1β expression

Sarah B. Matousek, Amy M. Hein, Solomon S. Shaftel, John A. Olschowka, Stephanos Kyrkanides, M. Kerry O'Banion

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Interleukin (IL)-1β is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL-1β include production of prostaglandin (PG) E2 by increasing expression of cyclooxygenase (COX) enzymes and prostaglandin E synthase (PGES) isoforms. We recently developed a transgenic mouse carrying a dormant human IL-1β eXcisional Activation Transgene (XAT) for conditional and chronic up-regulation of IL-1β in selected brain regions. This model is characterized by regionally specific glial activation, immune cell recruitment, and induction of cytokines and chemokines. Here, we aimed to elucidate the effects of long-term IL-1β expression on the PGE2 synthetic pathway and to determine the effects of PGs on inflammation and memory in our model. As expected, PGE2 levels were significantly elevated after IL-1β up-regulation. Quantitative real-time PCR analysis indicated significant induction of mRNAs for COX-1 and membranous PGES-1, but not COX-2 or other PGES isoforms. Immunohistochemistry revealed elevation of COX-1 but no change in COX-2 following sustained IL-1β production. Furthermore, pharmacological inhibition of COX-1 and use of COX-1 knockout mice abrogated IL-1β-mediated PGE2 increases. Although COX-1 deficient mice did not present a dramatically altered neuroinflammatory phenotype, they did exhibit improved contextual fear memory. This data suggests a unique role for COX-1 in mediating chronic neuroinflammatory effects through PGE2 production.

Original languageEnglish
Pages (from-to)247-258
Number of pages12
JournalJournal of Neurochemistry
Volume114
Issue number1
DOIs
StatePublished - Jul 2010

Keywords

  • Cyclooxygenase-1
  • Hippocampus
  • Interleukin-1
  • Neuroinflammation
  • Prostaglandin E

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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