TY - JOUR
T1 - Cyclooxygenase-1 mediates prostaglandin E2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1β expression
AU - Matousek, Sarah B.
AU - Hein, Amy M.
AU - Shaftel, Solomon S.
AU - Olschowka, John A.
AU - Kyrkanides, Stephanos
AU - O'Banion, M. Kerry
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
KW - Cyclooxygenase-1
KW - Hippocampus
KW - Interleukin-1
KW - Neuroinflammation
KW - Prostaglandin E
UR - http://www.scopus.com/inward/record.url?scp=77953304874&partnerID=8YFLogxK
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U2 - 10.1111/j.1471-4159.2010.06759.x
DO - 10.1111/j.1471-4159.2010.06759.x
M3 - Article
C2 - 20412387
AN - SCOPUS:77953304874
SN - 0022-3042
VL - 114
SP - 247
EP - 258
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 1
ER -