Cyclooxygenase-1 mediates prostaglandin E(2) elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1beta expression.
Interleukin (IL)-1beta is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL-1beta 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-1beta eXcisional Activation Transgene (XAT) for conditional and chronic up-regulation of IL-1beta 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-1beta 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-1beta 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-1beta production. Furthermore, pharmacological inhibition of COX-1 and use of COX-1 knockout mice abrogated IL-1beta-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.
Matousek
Sarah B
SB
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Hein
Amy M
AM
Shaftel
Solomon S
SS
Olschowka
John A
JA
Kyrkanides
Stephanos
S
O'Banion
M Kerry
MK
D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005239:Fear; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal
D016861:Cyclooxygenase Inhibitors; D053583:Interleukin-1beta; D051545:Cyclooxygenase 1; D015232:Dinoprostone
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