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Cyclooxygenase‐1 mediates prostaglandin E 2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin‐1β expression
Author(s) -
Matousek Sarah B.,
Hein Amy M.,
Shaftel Solomon S.,
Olschowka John A.,
Kyrkanides Stephanos,
O’Banion M. Kerry
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06759.x
Subject(s) - cyclooxygenase , proinflammatory cytokine , prostaglandin e , neuroinflammation , inflammation , prostaglandin e2 , genetically modified mouse , prostaglandin , cytokine , biology , prostaglandin h2 , hippocampal formation , transgene , eicosanoid , endocrinology , medicine , microbiology and biotechnology , immunology , enzyme , biochemistry , arachidonic acid , gene
J. Neurochem. (2010) 114 , 247–258. Abstract Interleukin (IL)‐1β is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL‐1β include production of prostaglandin (PG) E 2 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 PGE 2 synthetic pathway and to determine the effects of PGs on inflammation and memory in our model. As expected, PGE 2 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 PGE 2 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 PGE 2 production.