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1 Trauma Research and 2 Neurology Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013
Prostaglandin (PG) E2 is a principal downstream mediator of fever and other symptoms of systemic inflammation. Its inactivation occurs in peripheral tissues, primarily the lungs and liver, via carrier-mediated cellular uptake and enzymatic oxidation. We hypothesized that inactivation of PGE2 is suppressed during LPS fever and that transcriptional downregulation of PGE2 carriers and catabolizing enzymes contributes to this suppression. Fever was induced in inbred Wistar-Kyoto rats by intravenous LPS (50 µg/kg); the controls received saline. Samples of the liver, lungs, and hypothalamus were harvested 0, 0.5, 1.5, and 5 h postinjection. The expression of the two principal transmembrane PGE2 carriers (PG transporter and multispecific organic anion transporter) and the two key PGE2-inactivating enzymes [15-hydroxy-PG dehydrogenase (15-PGDH) and carbonyl reductase] was quantified by RT-PCR. All four genes of interest were downregulated in peripheral tissues (but not the brain) during fever. Most remarkably, the expression of hepatic 15-PGDH was decreased 26-fold 5 h post-LPS, whereas expression of pulmonary 15-PGDH was downregulated (as much as 18-fold) throughout the entire febrile course. The transcriptional downregulation of several proteins involved in PGE2 inactivation, first reported here, is an unrecognized mechanism of systemic inflammation. By increasing the blood-brain gradient of PGE2, this mechanism likely facilitates penetration of PGE2 into the brain and prevents its elimination from the brain.
systemic inflammation; multispecific organic anion transporter; prostaglandin transporter; 15-hydroxyprostaglandin dehydrogenase; carbonyl reductase
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